Review ArticleNatural Compounds as Regulators of NLRP3Inflammasome-Mediated IL-1120573 Production
Joacutezsef Tyzseacuter1 and Szilvia Benky2
1Department of Biochemistry and Molecular Biology Faculty of Medicine University of Debrecen Debrecen Hungary2Department of Physiology Faculty of Medicine University of Debrecen Debrecen Hungary
Correspondence should be addressed to Szilvia Benko benkoszmedunidebhu
Received 9 May 2016 Revised 18 July 2016 Accepted 11 August 2016
Academic Editor Alex Kleinjan
Copyright copy 2016 J Tozser and S Benko This is an open access article distributed under the Creative Commons AttributionLicense which permits unrestricted use distribution and reproduction in any medium provided the original work is properlycited
IL-1120573 is one of the main proinflammatory cytokines that regulates a broad range of immune responses and also participates inseveral physiological processes The canonical production of IL-1120573 requires multiprotein complexes called inflammasomes One ofthe most intensively studied inflammasome complexes is the NLRP3 inflammasome Its activation requires two signals one signalldquoprimesrdquo the cells and induces the expression of NLRP3 and pro-IL-1120573 while the other signal leads to the assembly and activationof the complex Several stimuli were reported to function as the second signal including reactive oxygen species lysosomal ruptureor cytosolic ion perturbation Despite very intensive studies the precise function and regulation of the NLRP3 inflammasome arestill not clear However many chronic inflammatory diseases are related to the overproduction of IL-1120573 that is mediated via theNLRP3 inflammasome In this review we aimed to provide an overview of studies that demonstrated the effect of plant-derivednatural compounds on NLRP3 inflammasome-mediated IL-1120573 production Although many of these studies lack the mechanisticexplanation of their action these compounds may be considered as complementary supplements in the treatment of chronicinflammatory diseases consumed as preventive agents and may also be considered as molecular tools to study NLRP3 function
1 Introduction
Inflammation is an important host response triggered byinvading pathogens or damaged tissues a response that isaimed at diluting or destroying the pathogens or isolating theinvolved site Moderate inflammatory response contributesto the host defense by removing pathogens or aiding inthe repair of damaged tissue However uncontrolled orprolonged inflammation may promote further tissue damageand could lead to serious disorders due to the overproductionof inflammatory cytokines
Among inflammatory mediators IL-1120573 is a master reg-ulatory cytokine functioning at several levels of immuneresponses such as activation of cells to produce other inflam-matory cytokines and chemokines induction of endothe-lial cells to express cell membrane adhesion molecules orassisting in the polarization of human Th17 cells [1ndash3]Furthermore it also participates in a variety of physiological
processes such as the regulation of synaptic plasticity andmemory processes in addition to participating in paindevelopment [4ndash7]
The production of IL-1120573 requires a multiprotein complexcalled inflammasome One of the most intensively studiedinflammasomes is the NLRP3 inflammasome that containsNLRP3 sensor ASC adaptor and caspase-1 protease [8]The presence of NLRP3 inflammasome has been shown notonly in immunocompetent cells but also in cells respon-sible for various physiological functions such as musclecells neurons or endocrine cells Upon stimulation NLRP3inflammasome components assemble into large cytoplasmiccomplexes and the activation of caspase-1 eventually leadsto the maturation and secretion of IL-1120573 Besides cytokineproduction NLRP3 inflammasome activation may also beaccompanied by caspase-1-mediated rapid cell death whichis known as pyroptosis [9]
Hindawi Publishing CorporationMediators of InflammationVolume 2016 Article ID 5460302 16 pageshttpdxdoiorg10115520165460302
2 Mediators of Inflammation
ERKp38
NLRP3
ASCNLRP3
Caspase-1ROS
ER stress
P2X7R ATP
Cathepsin B
TLR
ROS
mtDNA
Sirt2
AcAc
AcAc
AMPK
Cardio-lipin
Acetylated 120572-tubulin
Ca2+ influx
IL-1120573
Pro-IL-1120573
K+ efflux
120572-Tubulin
Pro-IL-1120573
NF120581B
Figure 1 Basic mechanisms of NLRP3 inflammasome activation
2 Mechanism of NLRP3 InflammasomeActivation
NLRP3 inflammasome can be activated by a broad range ofstimuli that belong either to pathogen-associated molecularpatterns (PAMPs) released during viral bacterial fungal orprotozoa infection [10ndash13] or to danger-associated molecularpatterns (DAMPs) of endogenous or exogenous origin likeextracellular ATP reactive oxygen species (ROS) choles-terol monosodium urate (MSU) crystals amyloid beta (A120573)plaques silica or asbestos [14ndash20] (Figure 1)
Due to the multiple functions of IL-1120573 production ofthis cytokine is tightly regulated requiring two signals Thefirst signal called ldquoprimingrdquo is mediated through PAMPsrecognized by specific receptors like TLRs activating signaltransduction pathways that induce the expression of theinflammasome components as well as that of the inactivecytokine precursor pro-IL-1120573 Signaling pathways throughNF120581B p38 and ERK1 have all been associated with theexpression of NLRP3 and pro-IL-1120573 [21ndash23] The secondsignal provided by DAMPs or PAMPs leads to the assemblyof the inflammasome complex that is followed by activationof caspase-1 and the cleavage and secretion of active IL-1120573 [24 25] Considering the diversity of the second signalssensed by NLRP3 it is highly unlikely that NLRP3 is capableof interacting directly with chemically different activatorsIt is more likely that NLRP3 senses a general signal thatinduces the sequential events of inflammasome activationSeveral cellular mechanisms were reported as requirementsfor activation including intracellular release of oxidizedmitochondrial DNA (mtDNA) increased intracellular Ca2+concentration decreased intracellular cAMP level or pore
formation by bacterial toxins [26ndash28] Common cellularevents are assumed to be critical for the inflammasomeactivation including ROS formation potassium (K+) effluxand cathepsin B leakage from lysosomes [29] Howeverdue to the controversial results published in the field theprecise mechanism that mediates NLRP3 inflammasomeactivation is still not known It is conceivable that morethan one single requirement needs to be fulfilled and theserequirements may depend on the activating stimuli also theper se characteristics of the stimulated cell
21 Reactive Oxygen Species Several NLRP3 inflammasomeactivating stimuli like nigericin or ATP induce oxidativestress and the production of intracellular ROS [15] Thesource of ROS is still unclear as some of the studiesreported the role of NADPH oxidase in ROS generation [30]while other studies proved that mitochondrial dysfunctionor ER stress leads to ROS production As a consequenceof mitochondrial dysfunction oxidized mtDNA is releasedwhich can activate NLRP3 inflammasome [26] eventuallyleading to IL-1120573 production It was also shown that incase of increased cytoplasmic ROS reduced thioredoxin(TRX) becomes oxidized and dissociates from thioredoxinbinding protein (TXNIP) that in turn binds to and acti-vates NLRP3 It was also shown that the expression ofTXNIP is upregulated during ER stress which also inducesNLRP3 activation [31] During oxidative stress misfoldedproteins accumulate which are sensed by the ERmembrane-bound inositol-requiring enzyme 1 (IRE1120572) and proteinkinase RNA-like endoplasmic reticulum kinase (PERK)In turn they initiate ER stress response activate NF120581Bpathways and induce the upregulation of TXNIP expres-sion [32] The role of nuclear factor- (rythroid-derived 2)
Mediators of Inflammation 3
like 2 (Nrf2) transcription factor-mediated antioxidant sig-naling pathway has also been reported as a negative regulatorof NLRP3 inflammasome as disruption of Nrf2 leads toincreased production of IL-1120573 [33] Recent works highlightthe importance ofmetabolic changes such as in glycolysis andoxidative phosphorylation that accompany cell activation andinfluence ROS production [34 35]Moreover ROS influencessignal transduction pathways such as NF120581B thus besidesNLRP3 inflammasome activation it is also thought to playa role in the ldquoprimingrdquo step [36]
22 Ion Flux and Perturbation Perturbation of cytosolic ionconcentration such as K+ and Ca2+ is a common resultof several NLRP inflammasome activating stimuli as manyactivators were shown to directly induce ion fluxes Nigericinor the activation of ATP-sensitive P2X7 receptor inducesrapid efflux of K+ [37ndash39] and K+ efflux has been provento act as a common signal to trigger NLRP3 inflammasomeactivation [40] Furthermore several pore forming toxinsresult in an increased intracellular Ca2+ that triggers NLRP3activation [41] Nevertheless changes in intracellular ionconcentration would also stimulate other inflammasomecomplexes which argues against ion flux as the exclusivecause for NLRP3 inflammasome activation
23 Lysosomal Rupture and Cathepsin B Release Destabi-lization of the acidic lysosomal compartment and release oflysosomal protease cathepsin B into the cytoplasm duringphagocytosis of large particles or crystals such as silicaasbestos uric acid or beta-amyloids have also been impli-cated in the activation of the NLRP3 inflammasome [42]Furthermore phagocytosis could also induce K+ effluxAdditionally lysosomes contain high concentration of Ca2+and lysosomal rupture results in the release of Ca2+ intothe cytosol triggering further Ca2+ release from the ERHowever the molecular details and connections of theseevents are not yet clarified In conclusion although NLRP3inflammasome is themost intensively studied inflammasomecomplex it is still unclear which mechanisms are responsiblefor its activation
24 Mitochondrial Dysfunction In response to infection orendogenous stimuli the perturbation of intracellular ROSK+ or lysosomal stability leads to mitochondrial dysfunctionand to the release of mitochondrial DAMPs such as mtDNAcardiolipin or dynamin-related protein 1 (Drp1) [43] Itwas shown that due to increased mtROS level releasedmtDNA is oxidized and activatesNLRP3 inflammasome [26]Cardiolipin is a non-bilayer-forming phospholipid foundin bacteria and in the inner mitochondrial membrane ofeukaryotes and its translocation from the inner membraneto the outer membrane was shown to activate NLRP3 inflam-masomedownstreamofmtROS [44] It was also reported thatGTPaseDrp1 that is needed for the fragmentation and aggre-gation of mitochondria also induces NLRP3 inflammasomeactivation and IL-1120573 secretion in response to VSV infectionbut not to ATP or nigericin [45] Moreover mitofusin anouter mitochondrial GTPase that regulates mitochondrial
fusion was also described as an NLRP3 activator duringviral infection [46] Recently it was described that themitochondrial antiviral signaling protein (MAVS) located inthemitochondrialmembranemediating interferon responsesalso induces NLRP3 inflammasome activation [47] Thesereports demonstrate that the mitochondrion is a complexregulator of cytosolic homeostasis and a central platform forNLRP3 inflammasome activation
25 Autophagy Autophagy is an evolutionarily conservedmechanism to maintain cellular homeostasis by selectivelyeliminating damaged or aging organelles microbes andubiquitinated proteins through the formation of autophago-somes and using lysosomal degradation Lines of evi-dence show that autophagy suppresses organelle stress-induced activation of NLRP3 inflammasome Furthermoreit was reported that inducers of autophagy also inducethe autophagosomal engulfment of IL-1120573 and its lysosomaldegradation [48] It was also shown that damaged mitochon-dria accumulate in autophagy-deficient macrophages that inturn lead to increased intracellular ROS and to the release ofmtDNA [49]
26 Spatial Location of NLRP3 Originally it was shownthat activated NLRP3 inflammasome localizes to the mito-chondria However recently it was described that duringinflammasome activation ER-associated NLRP3 colocalizeswith the mitochondria-associated ASC to the perinuclearspace via a microtubule-mediated organelle transport It wasshown that upon cell activation the decreased intracellularNAD+ level leads to the inhibition of sirtuin 2 (SIRT2)deacetylase resulting in the accumulation of acetylated alfa-tubulin triggering a dynein-dependent transport of mito-chondria to the perinuclear region into the close proximityto the ER [50]
3 NLRP3 Inflammasome and Related Diseases
Understanding the steps and mechanism of NLRP3 inflam-masome activation would be of crucial importance forthe treatment of several diseases in which the inflamma-some complex has been implicated By producing IL-1120573inflammatory cytokine and inducing pyroptosis the primaryfunction of NLRP3 inflammasome is to protect the hostfrom invading microorganisms [78] However nonmicrobialcompounds of either endogenous (self-derived) or exogenous(environmental) origin are also effective inducers of NLRP3inflammasome activation and lead to sterile inflammationallergic responses or other forms of inflammation [79] Forexample studies have shown that NLRP3 may be implicatedin Alzheimerrsquos disease suggesting that misfolded A120573 pro-teins form aggregates that lead to the activation of NLRPinflammasome [80 81] In gout MSU crystals from purinedegradation form deposits in different tissues and specif-ically activate NLRP3 inflammasome [14] Environmentalparticulates such as inhaled asbestos and silica also activateNLRP3 inflammasome and the high concentration of IL-1120573 is involved in the development of asbestosis and silico-sis two progressive pulmonary diseases leading to fibrosis
4 Mediators of Inflammation
[16 82] NLRP3 inflammasome has also been related toallergic responses to a variety of allergens such as aluminumdust mite or ragweed pollen however the molecular detailsof these responses are still not clear [83ndash85]
Other studies associated NLRP3 inflammasome functionwithmetabolic syndrome and type 2 diabetes as NLRP3 defi-cient mice were protected from high fat diet- (HFT-) inducedinflammation glucose intolerance insulin resistance andobesity [86 87]
The dysregulated production of IL-1120573 by the NLRP3inflammasome is the main reason for the development ofCryopyrin-Associated Periodic Syndromes (CAPS) which iscaused by a mutation in NLRP3 gene CAPS is an autoin-flammatory disorder rather than an autoimmune one assymptoms aremediated by the innate immune systemmainlyby monocytes and macrophages that produce huge amountof IL-1120573 Behcetrsquos disease (BD) is another chronic autoin-flammatory disorder of unknown etiology and increasedIL-1120573 production has been noted as a central player in thepathogenesis of this disease Studies demonstrated increasedROS production and consequently increased NLRP3 func-tion in these patients suggesting an important role forNLRP3inflammasome in mediating cytokine production [88] Inaddition to autoinflammatory diseases NLRP3 inflamma-some function has also been implicated in the developmentof autoimmune diseases like rheumatoid arthritis (RA) [89]RA is a common inflammatory disease affecting small jointsand our knowledge about its pathogenesis is still incompleteNevertheless elevated levels of IL-1120573 and high expression ofNLRP3 were detected from the serum and synovial tissue aswell as in macrophages of RA patients [90]
At present the role of NLRP3 inflammasome and IL-1120573 in cancer is highly controversial The microenvironmentof tumors is characterized by an inflammatory milieu thathelps tumor survival with growth hormones endothelialactivation and angiogenesis that leads to metastasis accom-panied by immune suppression IL-1120573 participates in each ofthese mechanisms by stimulating the expression of TNF120572MMPs VEGF ICAM-1 VCAM and so forth Cancer cellslike melanoma or myeloma as well as tumor-associatedmacrophages and dendritic cells were shown to contribute tothe IL-1120573 production that helps survival and growth of tumorcells furthermore excessive production of IL-1120573 can recruitimmunosuppressive cells like myeloid-derived suppressorscells (MDSCs) [91] On the other hand it was also shown thatNLRP3-induced IL-1120573 production boosts T cell function inpatients receiving chemotherapy [92]
The classical medical approach to treating the above-mentioned diseases involves the use of synthetic drugs devel-oped against individual elements of the signaling pathwaythe IL-1120573 cytokine or the IL-1120573 receptor as reviewed inOzaki et al 2015 [93] However today in the health-cautiouslife era the use of botanical and natural compounds hasgained popularity While a few decades ago the use of naturalcompounds was based exclusively on empirical experiencestoday with the highly developed molecular biological highthroughput methods many molecular elements of theiraction have already been identified However fundamentalquestions remain to be answered including bioavailability
effective doses body concentrations cross-reactivity half-life and degradation and synergistic effect of compoundsas well as carefully designed clinical trials The aim of thepresent review is to provide an overview of these plant-derived natural compounds that would support the use ofmedicinal plants (Figure 2) As a variety of compounds caninfluence inflammasome activation and function we havefocused on natural compounds that have been in long termuse in traditional medicine therefore their safety and overalleffect are mostly established However these compoundstypically influence a multitude of pathways and the exactmolecular mechanisms of their beneficial actions are notcompletely clarified (Table 1)
41 Aloe vera Aloe vera is a medical plant used traditionallyin diverse therapeutic applications The gel of Aloe verahas been reported to stimulate wound-healing and skinhydration induce hematopoiesis and possess antidiabeticanticarcinogenic antimicrobial and antioxidant as well asanti-inflammatory activities Over 75 active components havealready been identified in Aloe vera leaf gels [94] andsome of them have been implicated as immunomodulatorycompounds based on animal studies In amouse sepsismodeland in a human colorectal mucosa model treatment withAloe vera significantly inhibited the elevation of TNF120572 IL-6 and IL-1120573 levels [95 96] Studying human THP-1 cellsand human monocyte-derived macrophages it was foundthat Aloe vera treatment significantly reduced LPS-inducedIL-1120573 production [51] Aloe vera inhibited the expressionof pro-IL-1120573 NLRP3 and caspase-1 as well as that of theP2X7 receptor in the LPS-induced primary macrophagesFurthermore LPS-induced activation of signaling pathwayssuch as NF-120581B p38 JNK and ERK were inhibited by Aloevera in these cells [51]
Aloe emodin is an anthraquinone present naturally inAloe leaves It has been shown to promote natural killer cellactivity andmacrophage phagocytosis in tumor [97] Emodinitself appears to have some protective effect in the inflamma-tory response Recently it was shown that emodin attenuatednigericin- ATP- and silica-induced IL-1120573 secretion fromLPS-activated murine bone marrow-derived macrophages(BMDMs) It was also shown that mice treated intraperi-toneally with emodin showed higher survival rates than con-trol mice injected with LPS alone indicating that emodin canameliorate the severity of NLRP3 inflammasome-mediateddisease symptoms in vivo [52] However further moleculardetails of the inhibitory effect are yet to be discovered
42 Curcumin Curcumin is a lipid soluble polyphenol ayellow pigment isolated from the rhizomes of Curcuma longa(turmeric) but also found in other plants like ginger It iswidely used in food coloring and flavoring and it is also addedto cosmetics It has gained attention in recent years for itsmultiple pharmacological properties being antioxidant anti-inflammatory and antimicrobial as well as for its therapeutic
Mediators of Inflammation 5
O
O
OHOH
OH
Emodin
O O
OHHO
Curcumin
O
O
HO
OH
OH
OH
OHQuercetin
O
SN
CS
Sulforaphane
O
OH
OH
HHO
Genipin
O
O
O
OH
OH
OH
HO
OH
OH
OH
EGCG
O
O
O OH
OH
OH
OH
HO
HO
HOMangiferin
OH
OH
OH
OH
OGlc
OGlcGinsenoside
(basic)
OH
OH
OH
HO
OH
HO
Resveratrol
trans- cis-
H3C
H3CO
OCH3
OCH3
CH3
Figure 2 Chemical structure of natural compounds influencing NLRP3 inflammasome activation
potential in cancer autoimmune metabolic pulmonarycardiovascular and neurological diseases (reviewed in [98])
Brain ischemia is known to induce ER stress and inflam-matory responses leading to neuronal damage [99 100] Ina recent study glucose deprivation or hypoxia was reportedto strongly induce the production of glutamate and IL-1120573 inmouse hippocampus [53] It was shown that pretreatmentof the mouse hippocampus with curcumin reduced IL-1120573 production and this effect was attenuated by 51015840-AMP-activated protein kinase (AMPK) inhibitor suggesting thepossible involvement of AMPK The authors also foundthat curcumin attenuated glutamate-induced phosphoryla-tion of PERK and IRE1120572 the transmembrane sensors ofER stress that mediate inflammatory signals Moreoverusing a neuroblastoma cell line they showed that curcumininhibited glutamate-induced ROS generation as well asreduced glutamate-induced TXNIP expression As a possiblemolecular mechanism they found that in mice hippocam-pus glutamate stimulation increased NLRP3 expression andthe cleaved form of caspase-1 enzyme while curcuminattenuated NLRP3 and cleaved caspase-1 expression Theproduction of IL-6 a downstream target of IL-1120573 was alsoinhibited by curcumin treatment In addition curcumineffectively attenuated mitochondrial function and preventedcaspase-3 activation in hippocampus exposed to glutamate
stimulation effectively preventing glutamate-induced cellapoptosis Furthermore in rats curcumin administrationattenuated ischemic brain injury resulting from middlecerebral artery occlusion (MCAO) Based on these findingscurcumin activates AMPK that inhibits glutamate-inducedER stress and ROS production thus inhibiting TXNIP-induced NLRP3 inflammasome activation and ultimatelyreducing IL-1120573 production in mouse hippocampus limitingbrain injury
Macrophages are popular models for the study ofNLRP3 inflammasome activation In another study per-formed on mouse macrophage cell line J774A1 and peri-toneal macrophages curcumin was shown to strongly inhibitIL-1120573 secretion triggered by LPS plus nigericin aluminumATP or MSU [54] Preincubation with curcumin preventednigericin-induced intracellular potassium level decreaseattenuated lysosome damage and cathepsin B leakage andblocked high mobility group box 1 (HMGB-1) release need-less to say all of these are components that may induceNLRP3 inflammasome activation In BMDMs curcumininhibited nigericin- or aluminum crystal-induced ROS pro-duction The authors did not find obvious inhibitory effectof curcumin on JNK and p38 phosphorylation enhancedby nigericin treatment in the LPS-primed macrophageshowever they found that ERK12 phosphorylation was
6 Mediators of Inflammation
Table 1 Natural compounds effecting NLRP3 inflammasome-mediated IL-1 production
Compound Effect Mechanism Target cell Reference
Aloe vera extract Reduced IL-1120573
Reduced expression of NLRP3procaspase-1 and P2X7RInhibition of ERK p38 NF120581Bsignaling
THP-1 and human MF [51]
Aloe emodin Reduced IL-1120573 Reduced expression of NLRP3procaspase-1 and ASC expression BMDM [52]
Aloe emodin Enhanced survival NLRP3-KO mice model of septicshock [52]
Curcumin Reduced IL-1120573 andcaspase-1 inhibition Reduced ER stress through AMPK Mouse hippocampus [53]
Curcumin Reduced ROS and TXNIP expression Neuroblastoma cells [53]
Reduced expression of NLRP3 ASCand caspase-1Reduced ROS and reducedmitochondrial dysfunctionActivation of AMPK and autophagy
Murine hepatocytes [77]
dramatically downregulated In a mouse model of LPS-induced septic shock administration of curcumin signif-icantly decreased ROS level and cathepsin B leakage inperitoneal macrophages additionally peritoneal HMGB-1and IL-1120573 concentrations were downregulated resulting ina reduced LPS-induced splenomegaly These data suggestthat the observed reduction of secreted mature IL-1120573 bycurcumin is primarily attributed to the inhibition of NLRP3inflammasome activation
43 EGCG Epigallocatechin-3-gallate (EGCG) is the majorbioactive polyphenol in green tea that has a well-documentedantioxidant activity as it functions as a free-radical scavengerEGCG was reported to inhibit NF120581B activation and thesubsequent expression of several inflammatory moleculessuch as inducible nitric oxide synthase (iNOS) matrixmetalloproteinases (MMPs) IL-6 and TNF120572 Besides theanti-inflammatory role EGCG was also thought to possessantitumor effect [101]
In unilateral ureteral obstruction mice model renalinflammation has been linked to the activity of NLRP3inflammasome and the overproduction of IL-1120573 Further-more the role of NLRP3 inflammasome was proven in a vari-ety of human nondiabetic and chronic kidney diseases [102]It was reported that EGCG can prevent the development of
lupus nephritis when administered to NZBW F1 mice theclassical model of systemic lupus erythematosus [55] Thesestudies showed that EGCG treatment activated Nrf2 antiox-idant pathway induced the expression of Nrf2 downstreamenzymes like NAD(P)H dehydrogenase (quinone) 1 (NQO1)and heme oxygenase 1 (HO-1) and reduced renal oxidativestress Furthermore EGCG inhibited renal NLRP3 inflam-masome activity and the expressions of NLRP3 caspase-1and IL-1120573 were also reduced possibly due to the EGCG-induced attenuation of NF120581B pathway activity
Very recently the beneficial effect of EGCG was reportedin a contrast-inducednephropathy (CIN) ratmodel [56] CINis a common iatrogenic cause of acute kidney injury (AKI)after exposure to iodinated contrast medium characterizedby oxidative stress and inflammation [103] Similar to theprevious study they found that EGCG treatment reducedoxidative stress and increased Nrf2 and HO-1 expressionThey also found that EGCG reduced the elevated IL-1120573secretion and NLRP3 protein expression The molecularmechanisms of the observed results however were notstudied
44 Genipin Genipin is a water-soluble bifunctional cross-linking reagent that was initially isolated from the Chinesemedicinal plant Gardenia jasminoides (common name jas-mine) and it has been used for centuries as a herbal medicine
8 Mediators of Inflammation
to protect the liver and gallbladder It possesses antihyper-tensive antibleeding and antiswelling properties in additionto exhibiting anti-inflammatory characteristics Chemicallyit is an aglycone derived from an iridoid glycoside calledgeniposide that is enzymatically hydrolyzed to genipin byintestinal bacteria when administered per os [104] Genipinwas reported to inhibit mitochondrial uncoupling protein2 (UCP2) as well as superoxide-activated UCP2-mediatedproton leak occurring in a variety of diseases [105]
Recently it was shown that overexpression of UCP2caused a significant increase in NLRP3 expression in THP-1 cells and this was significantly inhibited by the adminis-tration of genipin while the levels of the adaptor proteinASC did not change [57] Interestingly genipin treatmentattenuated IL-1120573 levels in LPS-primed cells treated with ATPhowever this effect was not observed in cells treated withnigericin In addition it was also shown that inhibition ofATP-mediated inflammasome activation by genipin does notalter the production of other proinflammatory cytokines suchas IL-6 and TNF120572
In another recent study in LPS-primed murine BMDMsgenipin dramatically inhibited IL-1120573 secretion of LPS-primedcells following ATP nigericin MSU crystals or Listeriamonocytogenes treatment [58] Furthermore genipin alsoinhibited the Salmonella typhimurium-induced secretion ofIL-1120573 which is mediated via the activation of NLRC4inflammasome Similar to the previous study LPS-dependentTNF120572 secretion was not impaired by genipin Importantlygenipin treatment did not inhibit the expression of pro-IL-1120573 pro-caspase-1 or ASC proteins however it inhibitedNLRP3-dependent ASC oligomerization in addition to IL-1120573secretion and caspase-1 activation In contrast to its inhibitoryeffect on NLRP3-mediated ASC oligomerization genipindid not affect NLRC4-mediated formation of ASC speckleswhileNLRC4-mediated caspase-1 activationwas significantlydiminished These data indicate that the inhibitory effect ofgenipin on NLRC4 inflammasome activation is independentof ASC
45 Ginseng White ginseng is the naturally dried formof ginseng (Panax ginseng) while red ginseng is made bysteaming and drying fresh ginseng root Red ginseng hasbeen used for centuries as an immune-modulator and hasalso been used as an adjuvant in the treatment of infectiousand metabolic diseases Korean red ginseng contains variousactive components including saponins such as ginsenosidesand nonsaponins such as polysaccharides peptides fattyacids and mineral oils Ginsenosides are the major activecomponents of ginseng They reduce the production ofinflammatory cytokines by inhibiting NF120581B signaling [106]They also have amphiphilic nature and are able to intercalateinto the plasma membrane and influence membrane fluidityand function
It was shown that red ginseng extract (RGE) inhibitedATP- nigericin- and aluminum-induced IL-1120573 secretionin LPS-primed BMDMs and THP-1 cells and amelioratedlethality in LPS-induced septic shock model of mice [59]Furthermore RGE attenuated IL-1120573 secretion in dsDNA-transfected macrophages Similar results were obtained for
ginsenosides Furthermore it was also shown that RGE actedas an inhibitor of both NLRP3 and AIM2 inflammasomeactivations It was also demonstrated that RGE attenuated thesecretion of the active form of caspase-1 (p20)
It was previously reported that endogenousNOproducedby iNOS inhibits NLRP3 inflammasome activation via theS-nitrosylation of NLRP3 protein [107 108] A recent studyreported that ginsenosides negatively regulates LPS-inducedseptic shock in mice by a mechanism involving inhibitionof iNOS expression and the subsequent NO production[60] It was shown that ginsenosides reduced NO leveliNOS expression and ROS level in peritoneal macrophagesand BMDMs after LPS stimulation They also found thatginsenoside treatment attenuated S-nitrosylation of NLRP3protein which resulted in increased IL-beta secretion in LPS-activated macrophages
46 Mangiferin Mangiferin is a water-soluble naturalpolyphenol with a C-glycosylxanthone structure The pri-mary source of mangiferin is the mango tree (Mangiferaindica) however it is also present in some medicinal herbsin Iris unguicularis and in the honeybush a popular herbaltea from South Africa It possesses a wide spectrum ofbeneficial effects on health being used as an analgesicantidiabetic antisclerotic antimicrobial and antiviral as wellas being praised for its anti-inflammatory effects It has beenshown to regulate AMPK activity and in a recent work itwas reported that in human endothelial cells exposed tohigh glucose mangiferin reduced IL-1120573 secretion [61] Fur-thermore mangiferin attenuated IRE1 phosphorylation andreducedROS production and it decreased TXNIP expressionand inhibited ER stress Moreover a decrease in NLRP3expression and IL-1120573 production was also demonstrated
Very recently the protective role of mangiferin wasdescribed in LPS plus D-galactosamine- (D-GalN-) inducedacute liver injury [62] The authors showed that mangiferinreduced IL-1120573 secretion and ROS production and it alsoinhibited iNOS expression but induced Nrf2 and HO-1expression Furthermore it attenuated NLRP3 ASC andcaspase-1 (p10) expression and the subsequent IL-1120573 produc-tion
47 Propolis Propolis is a resinous material produced bybees (Apis mellifera L) through the mixing of secretions andenzymes from their hypopharyngeal glands with the budsof plants and wax A few hundred compounds have beendetected in raw propolis including polyphenols terpenoidssteroids sugar and amino acids Propolis composition islargely influenced by botanical origins and geographicallocation as well as by collection season One of the mostknown biological activities of propolis is related to its anti-inflammatory effect Artepillin C is a simple phenol com-posed of a single ring with two prenyl groups (35-diprenyl-4-hydroxycinnamic acid) and is the major biologically activephenolic ingredient identified in green propolis derived fromSoutheast Brazil [109]
The role of artepillin C was studied on the oxidativemetabolism of PMA-stimulated RAW2647 macrophages[63] It was shown that artepillin C significantly inhibited
Mediators of Inflammation 9
ROS release upon the NLRP3 activator nigericin treatment Itwas also suggested that artepillin C significantly contributedto the modulation of chemokine-mediated inflammation asit significantly downregulated the release of IL-1120573 IL-12p40and TNF120572 by LPS + IFN120574-treated RAW2647 cells whereasthe synthesis of IL-1120572 and IL-6 was not affected Besidesnigericin-mediated IL-1120573 production propolis also inhibitedLegionella pneumophila-induced IL-1120573 cytokine secretionin LPS-primed BMDMs This indicates that both NLRP3and NLRC4 inflammasome functions may be regulated bypropolis however further studies are required to clarify thedetailed molecular mechanism of the observed results
48 Quercetin Quercetin a kind of flavonoid found in avariety of vegetables beverages fruits and herbs exhibitsanti-inflammatory and antioxidant properties Quercetinwasreported to reduce inflammation in visceral adipose tissueprimary human adipocytes and the kidney of fructose-fedrats It was also shown to prevent diabetic kidney injury inratsHowever themechanisms of the action of quercetinwerenot clarified
It has been described that quercetin attenuated fructose-induced hyperuricemia and renal dysfunction In a studyusing streptozotocin- (STZ-) induced diabetic nephropa-thy rat model leading to hyperuricemia and dyslipidemiaquercetin was found to block NLRP3 inflammasome acti-vation [64] It was shown that the STZ-induced expres-sion of inflammasome components was restrained and IL-1120573 secretion was reduced by quercetin treatment Similarresults were obtained studying inflammatory responses infructose-induced hyperuricemia in rat [65] They showedthat fructose significantly elevated the expression of renalNLRP3 ASC and caspase-1 expression while quercetintreatment ameliorated the expression of these proteins Basedon their findings it was suggested that fructose-mediatedrenal NLRP3 inflammasome activation and proinflamma-tory cytokine overproduction may be associated with theimpaired cross talk between renal JAK2-STAT3 and PPAR-120572signaling pathway that in turn regulate renal inflammation
Furthermore it was shown that quercetin markedlyinhibited the overexpression of hepatic TXNIP in additionto reducing the production of ROS and the activation ofNLRP3 inflammasome consequently resulting in decreasedIL-1120573 secretion [66 110]They also showed that the decreasedcaspase-1 activity downregulated the caspase-1-dependentactivation of SREBPs that are involved in fatty acid andcholesterol synthesis They suggested that regulation of theTXNIP-NLRP3-SREBPs pathway by quercetin may partiallymediate the alleviation of hepatic steatosis in these diabeticrats
It was also shown that quercetin treatment regulatedAMPK pathway activation glutamine-glutamate cycle dys-function and TXNIP overexpression moreover it sup-pressed NF120581B pathway eventually leading to impairedNLRP3 inflammasome activation and IL-1120573 production inthe hypothalamus of high fructose- (HF-) fed rats [67]
Using human umbilical vein endothelial cells anothergroup reported that quercetin suppressed palmitate- (PA-) induced IL-1120573 and IL-6 induction [68] Downregulation
of NLRP3 induction was probably partially mediated viathe inhibition of ROS production and TXNIP expressionquercetin also inhibited IKK120573 activation by attenuatingits phosphorylation Furthermore quercetin treatment pro-tected cells against PA insult and significantly reduced thenumber of apoptotic cells Moreover quercetin amelioratedER stress-induced endothelial dysfunction through the acti-vation of AMPK
NLRP3 inflammasome is also recognized to have animportant role in the spinal cord tissue after traumatic spinalcord injury (SCI) and targeting the NLRP3 inflammasomecan inhibit neuroinflammation thereby improving func-tional recovery in SCI rats [111]
Very recently in a ratmodel of SCI quercetin administra-tion was shown to significantly improve functional recovery[69] Histopathological changes of the spinal cord such ascongestion edema neutrophil infiltration and structuraldisruption were inhibited by quercetin administration Toformulate a molecular mechanism the authors showed thatquercetin administration significantly reduced inflammatorycytokine IL-1120573 IL-18 and TNF120572 levels it also reduced theNLRP3 ASC and active caspase-1 protein expression andROS production However further studies are needed tobetter characterize the mechanisms of action underlying thebeneficial effects of quercetin in inflammation and immunity
49 Resveratrol Resveratrol is a polyphenol present inthe skin of grapes and mulberry commonly used in redwine production The beneficial effects of resveratrol arethought to be mediated in part by its antioxidant andanti-inflammatory properties exhibiting beneficial effectsin several diseases [112] Resveratrol exists as two isomerscis- and trans-resveratrol The cis isomer is thought to beproduced naturally during grape fermentation as a resultof isomerization of the trans isomer by yeast isomerasesFurthermore cis-resveratrol can be obtained by exposure ofthe trans isomer to sunlight Several studies have shown thattrans-resveratrol exhibits a wide range of biological activitiesincluding anti-inflammatory antioxidant anticarcinogenicantiaging antiplatelet aggregation immune-modulatory andchemoprevention effects However only few studies havebeen performed to examine the biological effects of the cisisomer Studies on cis-resveratrol have demonstrated thatit also possesses anticancer antimicrobial and antiplateletaggregation activities
One of the biological roles of resveratrol is to initiate theactivation of sirtuin 1 (Sirt1) is a deacetylase that modifies andinactivates inflammatory genes At high doses resveratrolhas been shown to activate AMPK which is involved inthe negative regulation of the NLRP3-inflammasome [113]It was also shown that ionizing radiation-induced IL-1120573secretion by human mesenchymal stem cells (MSCs) aneffect that was effectively abrogated by pretreatment withresveratrol [70] Radiation-induced increase in IL-1120573 occursvia the NLRP3 inflammasome activation however resver-atrol treatment attenuated the expression of NLRP3 It wasalso demonstrated that resveratrol treatment upregulated theexpression of Sirt1 In conclusion it is suggested that Sirt1
10 Mediators of Inflammation
inhibits NF120581B transcriptional activity through deacetylationthat in turn limits the transcription of NLRP3
In another study it was shown that cis-resveratrol pre-treatment significantly inhibited IL-1120573 secretion in THP-1 cellculture supernatants interestingly cis-resveratrol inducedIL-18 secretion under these conditions [71] Accordingly cis-resveratrol significantly reduced IL-1120573 mRNA expressionin contrast cis-resveratrol used at the same concentra-tion increased IL-18 mRNA expression Furthermore cis-resveratrol increased the mRNA and protein levels of NLRP1and NLRP3 indicating that the inhibitory effect of cis-resveratrol on IL-1120573 secretion is not due to the down-regulation of NLRP1 NLRP3 or ASC expression Similarresults were obtained on LPS-primed J774A1 macrophageswhere resveratrol inhibited the ATP-induced IL-1120573 secretionhowever in this study the authors did not find changes in theexpression of NLRP3 [72] showing that the resveratrol didnot inhibit the priming signal of NLRP3
Huang et al suggested that the inhibitory effect of cis-resveratrol on IL-1120573 secretion may be due to the reducedexpression of purinergic receptor P2X7R and the ER stressmarker GRP78 which leads to suppression of ROS pro-duction and reduced caspase-1 and caspase-4 activation Itwas found that cis-resveratrol also inhibited cyclooxygenase-(COX-) 2 expression which may be responsible for theobserved decrease of PGE2 production Furthermore inhi-bition of pro-IL-1120573 and COX-2 expression may occur bydownregulating the activation of the p38 MAPK path-way [71] Importantly in contrast to these observationsincreased phosphorylation of p38 was detected in ATP-activated J774A1 macrophages by Chang et al while itdid not significantly increase the phosphorylation levelsof ERK12 and it reduced the phosphorylation levels ofJNK12 The levels of mtDNA release into the cytosol weresignificantly reduced by resveratrol indicating that therewas less mitochondrial injury in resveratrol-treated cells[72] Furthermore the authors also showed that resveratrolincreased cellular cAMP level in J774A1 macrophages whichacts as a negative regulator of inflammatory responses andinhibits NLRP3 inflammasome activation
The effect of resveratrol on NLRP3 inflammasome wasfurther proved by a study showing that four weeks ofresveratrol administration inhibited the expression of NLRP3inflammasome components IL-1 IL-6 and TNF120572 and inlivers of HF-fed mice [73] They also showed that theregulatory effects of resveratrol on NLRP3 inflammasomemay come about through the combined effects of Sirt1 andSirt6
In a recent study [50] it was found that resveratroltreatment successfully suppressed the maturation of bothIL-1120573 and caspase-1 in response to Pam3CSK4 a TLR12agonist plus various inducers (like nigericin ATP MSUand silica) of the NLRP3-inflammasome In mouse BMDMshowever it did not affect the production of IL-1120573 medi-ated by the NLRC4-inflammasome (flagellin) or the AIM2-inflammasome (dsDNA) On a mouse model of acute goutthey indicated that resveratrol reduced the amount of matureIL-1120573 and the subsequent recruitment of neutrophils intothe peritoneal cavities of mice after challenge with MSU
crystals These findings indicate that resveratrol suppressesthe activation of the NLRP3-inflammasome both in vitroand in vivo As a possible mechanism they showed thatresveratrol at a substantially higher dosage successfullysuppressed mitochondrial ROS production Furthermoreresveratrol treatment prevented the accumulation of acety-lated 120572-tubulin thusinhibiting the proximate localization ofASC and NLRP3 in macrophages
In a very recent publication [74] the authors showed thatresveratrol preventedATP-inducedNLRP3 activation and IL-1120573 production in the BV2 cell line and in septic mice as wellThey also found that resveratrol treatment reduced NLRP3and IL-1120573 expression in the hippocampus of the mice andthey suggested that the protecting effect of resveratrol wasmediated via the increased expression of Sirt1 in BV2 cells
Another recent publication found that glucose-basedperitoneal dialysis increased mitochondrial ROS productionand subsequent IL-1120573 secretion through NLRP3 inflamma-some in human peritoneal mesothelial cells (HPMC) Asa mechanism for its action they showed that resveratrolinduced mitophagyautophagy of the cells via AMPK activa-tion and protected cells fromROS-inducedNLRP3-mediatedinflammatory injury [75]
410 Sulforaphane Sulforaphane (SFN) is a natural com-pound present in cruciferous vegetables such as broccolicabbage Brussel sprouts mustard and radish ChemicallySFN is an isothiocyanate that is known to react withsulfhydryl groups and tomodify proteins at cysteine residuesSulforaphane is produced from the precursor glucoraphaninby the enzymatic activity of myrosinase when the cell wallsof the plant are damaged for example during chewingSFN has been known as a cytoprotective agent for cancerprevention or treatment and it also has an important rolein cardiovascular neurologic and other diseases (reviewedin [114]) SFN is a known inducer of the Nrf2 antioxidantpathway as it activates the Nrf2 transcription factor byreacting with cysteine residues of its repressor Keap1 [115]In addition it also inhibits NF120581B signaling [116]
It was shown that SFN inhibited IL-1120573 processing byNLRP1- NLRP3- NLRC4- and AIM2- inflammasome com-plexes in mouse BMDMs [28] It was also demonstratedthat SFN inhibits the inflammasome in an Nrf2-independentmanner as SFN-mediated inhibition of NLRP3- andNLRC4-dependent IL-1120573 processing and secretion was not reversedin Nrf2-knockout BMDMs When SFN was added directlyto the cell lysates it did not inhibit IL-1120573 processingdemonstrating that SFN does not directly inhibit the proteaseactivity of caspase-1 The authors found that SFN-mediatedinhibition of the inflammasomes is not affected by ROSmodulation and neither proteasome-dependent proteolysisnor de novo protein synthesis is required for SFN-mediatedinhibition of the inflammasomes In a peritonitis model ofacute gout SFN treatment significantly reducedMSU crystal-induced IL-1120573 production demonstrating that SFN inhibitsthe NLRP3 inflammasome function in vivo Nonethelessthe authors concluded that SFN inhibits multiple inflam-masomes in vitro and in vivo by a mechanism independent
Mediators of Inflammation 11
ERKp38
NLRP3
ASCNLRP3
Caspase-1ROS
ER stress
P2X7R ATP
Cathepsin B
TLR
ROS
mtDNA
Sirt2
AcAc
AcAc
AMPK
A
A AC
C
C
Nrf2E
E
UCP2Ge
Ge
Ge
Gi
TXNIPC
NOGi
P
Sirt1R
R
R
R
M
M
M
Q
QQ
SS
S
R
Cardio-lipin
Acetylated 120572-tubulin
Ca2+ influx
IL-1120573
Pro-IL-1120573
K+efflux
120572-Tubulin
Pro-IL-1120573
NF120581B
Figure 3 Molecular targets of natural compounds affecting NLRP3 inflammasome-mediated IL-1 production
of inflammasome priming and Nrf2 signaling however theexact molecular mechanism was not explored
As SFN is able to penetrate the blood-brain barrier[117] it gained a considerable attention as a candidatefor Alzheimerrsquos disease (AD) therapy SFN was shown toprotect the brain from A120573-induced oxidative cell death viaactivation of Nrf2 signaling cascade [118] As A120573 fibrilshave been shown to activate NLRP3 inflammasome thequestion arose whether SFN may regulate this mechanismIn a very recent study it was shown that SFN significantlydownregulated IL-1120573 production and NLRP3 expression inA1205731ndash42 peptide-stimulated human THP-1 cells macrophages[76] It was found that A1205731ndash42 peptide-induced STAT-1phosphorylation was significantly attenuated by SFN Theauthors showed that SFN inducedNrf2 nuclear translocationwhich was subsequently accompanied by an increase in HO-1 protein levels Furthermore A1205731ndash42 peptide-induced IL-1120573 production was diminished by siRNA-mediated knock-down of Nrf2 or HO-1 They also found that the increasedproinflammatory miRNA-146a level following A1205731ndash42 treat-ment was significantly attenuated by SFN whereas miRNA-125b and miRNA-155 levels were not changed These arespecific proinflammatory miRNAs that were reported to beincreased in both the extracellular fluid and cerebrospinalfluid of AD patients In conclusion SFN can suppress A1205731ndash42-induced caspase-1-dependent inflammasome activationpossibly through inhibiting STAT-1 phosphorylation andactivation of the Nrf2HO-1 signaling pathway
Also very recently another research group reported thatoral administrations of SFN suppressed the saturated fattyacid-induced NLRP3 inflammasome activation in the liverof mice [77] They found that SFN decreased the expression
of ASC caspase-1 and IL-1120573 levels additionally it inhibitedthe activity of caspase-1 enzyme in primary hepatocytes Itwas also shown that SFN reduced the palmitate-inducedROS production by the mitochondria implying that SFNprevented mitochondrial dysfunction and this protectingmechanism was in part mediated by the activation of AMPKThey concluded that activation of AMPK and autophagy bySFN could protect from mitochondrial dysfunction inducedby saturated fatty acids resulting in a downregulation of fat-induced activation of the NLRP3 inflammasome
5 NLRP3 Inflammasome and theXenohormesis Hypothesis
As it was described in detail above polyphenols like resvera-trol curcumin EGCG and quercetin are potent inhibitors ofNLRP3 inflammasome-mediated IL-1120573 production typicallyacting at more than one element of the involved pathways(Figure 3)However it should be noted that these polyphenolshave an evenmuch broader biological effect as they influencea variety of pathways [119] though not all are directlyconnected to the function of the NLRP3 inflammasomeImportantly more than 8000 natural polyphenols have beendescribed [120] providing a large library of compounds aspotential inflammasome inhibitors Many of these polyphe-nols (such as resveratrol and curcumin) are overproducedby stressed plants triggering pathways mimicking the effectof caloric restriction It has been proposed that organismsfrom yeast to humans consuming stressed plants couldinterpret the stress signal carried by such polyphenols as apotential risk of future limitation of food availability and in
12 Mediators of Inflammation
turn adapting for the pursuit of longevity a theory termedas Xenohormesis [121ndash123] Interestingly the structurallyunrelated resveratrol and curcumin can achieve this caloricrestriction mimicking effect by activating AMPK and Sirt1[124] However polyphenols are also known to have anantioxidant effect activate glutathione S-transferases andinhibit COX enzymes among many other effects [125 126]Interestingly one of the most frequently used COX inhibitoris aspirin a derivative of another stress-induced phytochem-ical salicylic acid
A major concern of polyphenol use in therapy is thebioavailability of these compounds Nevertheless typicaldietary polyphenol intake is about 14mgkgday which iswithin the range of providing biologically active doses [127]
6 Concluding Remarks
Most of the time inflammasome-mediated IL-1120573 productionor caspase-mediated pyroptosis is beneficial for the host as itprotects from infection or prevents further damageHoweverprolonged cytokine production as in the case of sterileinflammation caused by endogenous danger signals maylead to the development of autoinflammatory or metabolicdiseases Chronic inflammation compromises the hostrsquos lifequality and requires sustained pharmacological and surgicaltreatments The paradigm of drug discovery in Westernmedicine is to develop highly selective compounds againstindividual druggable targets Currently the main treatmentmethods for these patients are targeting IL-1120573 Howeverprolonged usage of drugs may induce different side effectsfurthermore some form of medications are very expensivewhich limits their widespread use
Besides the high expenses another drawback of tradi-tional drug design is that many of the promising compoundsfail in the early or later stages of drug development Tradi-tional medicine uses many plant products to treat diseaseshowever the exact mechanisms behind their use is stillmostly lacking partially as a consequence of the pleiotropiceffect of the active compounds as detailed in this reviewNevertheless clarification of the molecular mechanism ofaction of such natural compounds already used in traditionalmedicine for quite some time will undoubtedly aid in theproduction of safe and cheap candidate medications to beused in the treatment of diseases including those appearingas a consequence of NLRP3 inflammasome-mediated IL-1120573overproduction
Competing Interests
The authors declare no conflict of interests
Acknowledgments
This work was supported by OTKA-K 109429 Szilvia Benkois a receiver of Lajos Szodoray Postdoctoral Fellowship andJanos Bolyai Postdoctoral Fellowship
References
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[2] G Meng F Zhang I Fuss A Kitani and W Strober ldquoA muta-tion in the Nlrp3 gene causing inflammasome hyperactivationpotentiates Th17 cell-dominant immune responsesrdquo Immunityvol 30 no 6 pp 860ndash874 2009
[3] D Lasiglie E Traggiai S Federici et al ldquoRole of IL-1 beta in thedevelopment of human TH17 cells lesson fromNLPR3mutatedpatientsrdquo PLoS ONE vol 6 no 5 Article ID e20014 2011
[4] H Schneider F Pitossi D Balschun A Wagner A Del Reyand H O Besedovsky ldquoA neuromodulatory role of interleukin-1120573 in the hippocampusrdquo Proceedings of the National Academy ofSciences of the United States of America vol 95 no 13 pp 7778ndash7783 1998
[5] E Gabay G Wolf Y Shavit R Yirmiya and M Tal ldquoChronicblockade of interleukin-1 (IL-1) prevents and attenuates neuro-pathic pain behavior and spontaneous ectopic neuronal activityfollowing nerve injuryrdquo European Journal of Pain vol 15 no 3pp 242ndash248 2011
[6] A del Rey A V Apkarian M Martina and H O BesedovskyldquoChronic neuropathic pain-like behavior and brain-borne IL-1120573rdquo Annals of the New York Academy of Sciences vol 1262 no 1pp 101ndash107 2012
[7] R Yirmiya and I Goshen ldquoImmune modulation of learningmemory neural plasticity and neurogenesisrdquo Brain Behaviorand Immunity vol 25 no 2 pp 181ndash213 2011
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[36] F Bauernfeind E Bartok A Rieger L Franchi G Nunez andV Hornung ldquoCutting edge reactive oxygen species inhibitorsblock priming but not activation of the NLRP3 inflamma-somerdquo The Journal of Immunology vol 187 no 2 pp 613ndash6172011
[37] D Perregaux and C A Gabel ldquoInterleukin-1 beta maturationand release in response to ATP and nigericin Evidence thatpotassium depletion mediated by these agents is a necessaryand common feature of their activityrdquoThe Journal of BiologicalChemistry vol 269 no 21 pp 15195ndash15203 1994
[38] J M Kahlenberg K C Lundberg S B Kertesy Y Qu and GR Dubyak ldquoPotentiation of caspase-1 activation by the P2X7receptor is dependent on TLR signals and requires NF-120581B-driven protein synthesisrdquo Journal of Immunology vol 175 no11 pp 7611ndash7622 2005
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[41] T Murakami J Ockinger J Yu et al ldquoCritical role for calciummobilization in activation of the NLRP3 inflammasomerdquo Pro-ceedings of the National Academy of Sciences of the United Statesof America vol 109 no 28 pp 11282ndash11287 2012
[42] V Hornung F Bauernfeind A Halle et al ldquoSilica crystals andaluminum salts activate the NALP3 inflammasome throughphagosomal destabilizationrdquo Nature Immunology vol 9 no 8pp 847ndash856 2008
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[45] X Wang W Jiang Y Yan et al ldquoRNA viruses promoteactivation of the NLRP3 inflammasome through a RIP1-RIP3-DRP1 signaling pathwayrdquoNature Immunology vol 15 no 12 pp1126ndash1133 2014
[46] T Ichinohe T Yamazaki T Koshiba and Y Yanagi ldquoMitochon-drial protein mitofusin 2 is required for NLRP3 inflammasomeactivation afterRNAvirus infectionrdquoProceedings of theNationalAcademy of Sciences of the United States of America vol 110 no44 pp 17963ndash17968 2013
[47] N Subramanian K Natarajan M R Clatworthy Z Wangand R N Germain ldquoThe adaptor MAVS promotes NLRP3mitochondrial localization and inflammasome activationrdquo Cellvol 153 no 2 pp 348ndash361 2013
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14 Mediators of Inflammation
moleculesrdquo ACS Chemical Biology vol 8 no 12 pp 2724ndash27332013
[49] K Nakahira J A Haspel V A K Rathinam et al ldquoAutophagyproteins regulate innate immune responses by inhibiting therelease of mitochondrial DNA mediated by the NALP3 inflam-masomerdquo Nature Immunology vol 12 no 3 pp 222ndash230 2011
[50] T Misawa M Takahama T Kozaki et al ldquoMicrotubule-drivenspatial arrangement ofmitochondria promotes activation of theNLRP3 inflammasomerdquo Nature Immunology vol 14 no 5 pp454ndash460 2013
[51] M M Budai A Varga S Milesz J Tozser and S BenkoldquoAloe vera downregulates LPS-induced inflammatory cytokineproduction and expression of NLRP3 inflammasome in humanmacrophagesrdquo Molecular Immunology vol 56 no 4 pp 471ndash479 2013
[52] J-W Han D-W Shim W-Y Shin et al ldquoAnti-inflammatoryeffect of emodin via attenuation of NLRP3 inflammasomeactivationrdquo International Journal of Molecular Sciences vol 16no 4 pp 8102ndash8109 2015
[53] Y Li J Li S Li et al ldquoCurcumin attenuates glutamate neurotox-icity in the hippocampus by suppression of ER stress-associatedTXNIPNLRP3 inflammasome activation in a manner depen-dent onAMPKrdquoToxicology andApplied Pharmacology vol 286no 1 pp 53ndash63 2015
[54] Z Gong J Zhou H Li et al ldquoCurcumin suppresses NLRP3inflammasome activation and protects against LPS-inducedseptic shockrdquo Molecular Nutrition and Food Research vol 59no 11 pp 2132ndash2142 2015
[55] P-Y Tsai S-M Ka J-M Chang et al ldquoEpigallocatechin-3-gallate prevents lupus nephritis development in mice viaenhancing the Nrf2 antioxidant pathway and inhibiting NLRP3inflammasome activationrdquo Free Radical Biology and Medicinevol 51 no 3 pp 744ndash754 2011
[56] Z Gao Y Han Y Hu et al ldquoTargeting HO-1 byepigallocatechin-3-gallate reduces contrast-induced renalinjury via anti-oxidative stress and anti-inflammationpathwaysrdquo PLOS ONE vol 11 no 2 article e0149032 2016
[57] V Rajanbabu L Galam J Fukumoto et al ldquoGenipin suppressesNLRP3 inflammasome activation through uncoupling protein-2rdquo Cellular Immunology vol 297 no 1 pp 40ndash45 2015
[58] S-X Yu C-T DuW Chen et al ldquoGenipin inhibits NLRP3 andNLRC4 inflammasome activation via autophagy suppressionrdquoScientific Reports vol 5 article 17935 2015
[59] J Kim H Ahn B-C Han et al ldquoKorean red ginseng extractsinhibit NLRP3 and AIM2 inflammasome activationrdquo Immunol-ogy Letters vol 158 no 1-2 pp 143ndash150 2014
[60] S-J Yoon J-Y Park S Choi et al ldquoGinsenoside Rg3 regulatesS-nitrosylation of the NLRP3 inflammasome via suppression ofiNOSrdquo Biochemical and Biophysical Research Communicationsvol 463 no 4 pp 1184ndash1189 2015
[61] J Song J Li F Hou X Wang and B Liu ldquoMangiferininhibits endoplasmic reticulum stress-associated thioredoxin-interacting proteinNLRP3 inflammasome activation with reg-ulation of AMPK in endothelial cellsrdquo Metabolism vol 64 no3 pp 428ndash437 2015
[62] C-W Pan Z-Z Pan J-J Hu et al ldquoMangiferin alleviateslipopolysaccharide and D-galactosamine-induced acute liverinjury by activating the Nrf2 pathway and inhibiting NLRP3inflammasome activationrdquo European Journal of Pharmacologyvol 770 pp 85ndash91 2016
[63] J I Hori D S Zamboni D B Carrao GHGoldman andAABerretta ldquoThe inhibition of inflammasome by Brazilian propo-lis (EPP-AF)rdquo Evidence-Based Complementary and AlternativeMedicine vol 2013 Article ID 418508 11 pages 2013
[64] C Wang Y Pan Q-Y Zhang F-M Wang and L-D KongldquoQuercetin and allopurinol ameliorate kidney injury in STZ-treated rats with regulation of renal NLRP3 inflammasomeactivation and lipid accumulationrdquo PLoS ONE vol 7 no 6Article ID e38285 2012
[65] Q-H Hu X Zhang Y Pan Y-C Li and L-D Kong ldquoAllop-urinol quercetin and rutin ameliorate renal NLRP3 inflamma-some activation and lipid accumulation in fructose-fed ratsrdquoBiochemical Pharmacology vol 84 no 1 pp 113ndash125 2012
[66] WWangCWangX-QDing et al ldquoQuercetin and allopurinolreduce liver thioredoxin-interacting protein to alleviate inflam-mation and lipid accumulation in diabetic ratsrdquo British Journalof Pharmacology vol 169 no 6 pp 1352ndash1371 2013
[67] Q-Y Zhang Y Pan R Wang et al ldquoQuercetin inhibitsAMPKTXNIP activation and reduces inflammatory lesions toimprove insulin signaling defect in the hypothalamus of highfructose-fed ratsrdquo Journal of Nutritional Biochemistry vol 25no 4 pp 420ndash428 2014
[68] J Wu X Xu Y Li et al ldquoQuercetin luteolin and epigallo-catechin gallate alleviate TXNIP and NLRP3-mediated inflam-mation and apoptosis with regulation of AMPK in endothelialcellsrdquo European Journal of Pharmacology vol 745 pp 59ndash682015
[69] W Jiang Y Huang N Han et al ldquoQuercetin suppresses NLRP3inflammasome activation and attenuates histopathology in a ratmodel of spinal cord injuryrdquo Spinal Cord vol 54 pp 592ndash5962016
[70] Y Fu Y Wang L Du et al ldquoResveratrol inhibits ionisingirradiation-induced inflammation in MSCs by activating Sirt1and limiting NLRP-3 inflammasome activationrdquo InternationalJournal ofMolecular Sciences vol 14 no 7 pp 14105ndash14118 2013
[71] T-T Huang H-C Lai Y-B Chen et al ldquoCis-Resveratrolproduces anti-inflammatory effects by inhibiting canonicaland non-canonical inflammasomes in macrophagesrdquo InnateImmunity vol 20 no 7 pp 735ndash750 2014
[72] Y-P Chang S-M Ka W-H Hsu et al ldquoResveratrol inhibitsNLRP3 inflammasome activation by preserving mitochondrialintegrity and augmenting autophagyrdquo Journal of Cellular Physi-ology vol 230 no 7 pp 1567ndash1579 2015
[73] S J Yang and Y Lim ldquoResveratrol ameliorates hepaticmetaflammation and inhibits NLRP3 inflammasome activa-tionrdquoMetabolism vol 63 no 5 pp 693ndash701 2014
[74] D-M Sui Q Xie W-J Yi et al ldquoResveratrol protects againstsepsis-associated encephalopathy and inhibits the NLRP3IL-1 120573 axis in microgliardquo Mediators of Inflammation vol 2016Article ID 1045657 10 pages 2016
[75] J Wu X Li G Zhu Y Zhang M He and J Zhang ldquoTherole of Resveratrol-inducedmitophagyautophagy in peritonealmesothelial cells inflammatory injury via NLRP3 inflamma-some activation triggered bymitochondrial ROSrdquoExperimentalCell Research vol 341 no 1 pp 42ndash53 2016
[76] Y W An K A Jhang S Y Woo J L Kang and Y HChong ldquoSulforaphane exerts its anti-inflammatory effectagainst amyloid-120573 peptide via STAT-1 dephosphorylationand activation of Nrf2HO-1 cascade in human THP-1macrophagesrdquo Neurobiology of Aging vol 38 pp 1ndash10 2016
[77] G Yang H E Lee and J Y Lee ldquoA pharmacological inhibitorof NLRP3 inflammasome prevents non-alcoholic fatty liver
Mediators of Inflammation 15
disease in a mouse model induced by high fat dietrdquo ScientificReports vol 6 Article ID 24399 2016
[78] L Franchi R Munoz-Planillo and G Nunez ldquoSensing andreacting to microbes through the inflammasomesrdquo NatureImmunology vol 13 no 4 pp 325ndash332 2012
[79] S L Cassel and F S Sutterwala ldquoSterile inflammatory responsesmediated by the NLRP3 inflammasomerdquo European Journal ofImmunology vol 40 no 3 pp 607ndash611 2010
[80] M-S Tan J-T Yu T Jiang X-C Zhu and L Tan ldquoThe NLRP3inflammasome in alzheimerrsquos diseaserdquoMolecular Neurobiologyvol 48 no 3 pp 875ndash882 2013
[81] M Gold and J El Khoury ldquo120573-amyloid microglia andthe inflammasome in Alzheimerrsquos diseaserdquo Seminars inImmunopathology vol 37 no 6 pp 607ndash611 2015
[82] P M Peeters T N Perkins E F M Wouters B T Mossmanand N L Reynaert ldquoSilica induces NLRP3 inflammasomeactivation in human lung epithelial cellsrdquo Particle and FibreToxicology vol 10 no 1 article 3 2013
[83] H Watanabe O Gaide V Petrilli et al ldquoActivation of the IL-1120573-processing inflammasome is involved in contact hypersen-sitivityrdquo Journal of Investigative Dermatology vol 127 no 8 pp1956ndash1963 2007
[84] X Dai K Sayama M Tohyama et al ldquoMite allergen is adanger signal for the skin via activation of inflammasome inkeratinocytesrdquo Journal of Allergy and Clinical Immunology vol127 no 3 pp 806ndash814 2011
[85] A Varga M M Budai S Milesz A Bacsi J Tozser and SBenko ldquoRagweed pollen extract intensifies lipopolysaccharide-induced priming of NLRP3 inflammasome in humanmacrophagesrdquo Immunology vol 138 no 4 pp 392ndash4012013
[86] B Vandanmagsar Y-H Youm A Ravussin et al ldquoThe NLRP3inflammasome instigates obesity-induced inflammation andinsulin resistancerdquo Nature Medicine vol 17 no 2 pp 179ndash1892011
[87] H Wen D Gris Y Lei et al ldquoFatty acid-induced NLRP3-ASCinflammasome activation interferes with insulin signalingrdquoNature Immunology vol 12 no 5 pp 408ndash415 2011
[88] L Liang X Tan Q Zhou et al ldquoIL-1120573 triggered by pepti-doglycan and lipopolysaccharide through TLR24 and ROS-NLRP3 inflammasome- dependent pathways is involved inocular behcetrsquos diseaserdquo Investigative Ophthalmology and VisualScience vol 54 no 1 pp 402ndash414 2013
[89] S Rosengren H M Hoffman W Bugbee and D L BoyleldquoExpression and regulation of cryopyrin and related proteinsin rheumatoid arthritis synoviumrdquo Annals of the RheumaticDiseases vol 64 no 5 pp 708ndash714 2005
[90] J M Kahlenberg ldquoAnti-inflammatory panaceaThe expandingtherapeutics of interleukin-1 blockaderdquo Current Opinion inRheumatology vol 28 no 3 pp 197ndash203 2016
[91] C-H Chien M-J Lee H-C Liou H-H Liou and W-MFu ldquoLocal immunosuppressive microenvironment enhancesmigration of melanoma cells to lungs in DJ-1 knockout micerdquoPLoS ONE vol 10 no 2 Article ID e0115827 2015
[92] C Antonopoulos and G R Dubyak ldquoChemotherapy engagesmultiple pathways leading to IL-1120573 production by myeloidleukocytesrdquo OncoImmunology vol 3 no 1 Article ID e274992014
[93] E Ozaki M Campbell and S L Doyle ldquoTargeting the NLRP3inflammasome in chronic inflammatory diseases current per-spectivesrdquo Journal of Inflammation Research vol 8 pp 15ndash272015
[94] J H Hamman ldquoComposition and applications of Aloe vera leafgelrdquoMolecules vol 13 no 8 pp 1599ndash1616 2008
[95] L Langmead R J Makins and D S Rampton ldquoAnti-inflammatory effects of aloe vera gel in human colorectalmucosa in vitrordquo Alimentary Pharmacology and Therapeuticsvol 19 no 5 pp 521ndash527 2004
[96] N Yun C-H Lee and S-M Lee ldquoProtective effect of Aloe veraon polymicrobial sepsis inmicerdquo Food andChemical Toxicologyvol 47 no 6 pp 1341ndash1348 2009
[97] C S Yu F S Yu J K Chan et al ldquoAloe-emodin affects the levelsof cytokines and functions of leukocytes from Sprague-Dawleyratsrdquo In Vivo vol 20 no 4 pp 505ndash509 2006
[98] M Pulido-Moran J Moreno-Fernandez C Ramirez-Tortosaand M Ramirez-Tortosa ldquoCurcumin and healthrdquo Moleculesvol 21 no 3 article E264 2016
[99] Y-F Dong L-X Wang X Huang et al ldquoKir61 knock-down aggravates cerebral ischemiareperfusion-induced neuralinjury in micerdquo CNS Neuroscience and Therapeutics vol 19 no8 pp 617ndash624 2013
[100] P J Maier K Zemoura M A Acuna G E Yevenes HU Zeilhofer and D Benke ldquoIschemia-like oxygen and glu-cose deprivation mediates down-regulation of cell surface 120574-aminobutyric acidB receptors via the endoplasmic reticulum(ER) stress-induced transcription factor CCAATenhancer-binding protein (CEBP)-homologous protein (CHOP)rdquo TheJournal of Biological Chemistry vol 289 no 18 pp 12896ndash129072014
[101] H-Y Shin S-H Kim H-J Jeong et al ldquoEpigallocatechin-3-gallate inhibits secretion of TNF-120572 IL-6 and IL-8 through theattenuation of ERK and NF-120581B in HMC-1 cellsrdquo InternationalArchives of Allergy and Immunology vol 142 no 4 pp 335ndash3442007
[102] W P Pulskens L M Butter G J Teske et al ldquoNlrp3 preventsearly renal interstitial edema and vascular permeability inunilateral ureteral obstructionrdquo PLoS ONE vol 9 no 1 ArticleID e85775 2014
[103] S Kamath and C A Roobottom ldquoHyperdense pericardial effu-sion in dermatomyositis and contrast induced nephropathyrdquoEmergency Radiology vol 11 no 3 pp 177ndash179 2005
[104] T Akao K Kobashi and M Aburada ldquoEnzymic studies onthe animal and intestinal bacterial metabolism of geniposiderdquoBiological and Pharmaceutical Bulletin vol 17 no 12 pp 1573ndash1576 1994
[105] R Wang K C MoYung M H Zhang and K Poon ldquoUCP2-and non-UCP2-mediated electric current in eukaryotic cellsexhibits different propertiesrdquo Environmental Science and Pollu-tion Research vol 22 no 24 pp 19618ndash19631 2015
[106] J-M Lu Q Yao and C Chen ldquoGinseng compounds an updateon their molecular mechanisms and medical applicationsrdquoCurrent Vascular Pharmacology vol 7 no 3 pp 293ndash302 2009
[107] E Hernandez-Cuellar K Tsuchiya H Hara et al ldquoCuttingedge nitric oxide inhibits the NLRP3 inflammasomerdquo TheJournal of Immunology vol 189 no 11 pp 5113ndash5117 2012
[108] B B Mishra V A K Rathinam G W Martens et alldquoNitric oxide controls the immunopathology of tuberculosis byinhibiting NLRP3 inflammasome-dependent processing of IL-1120573rdquo Nature Immunology vol 14 no 1 pp 52ndash60 2013
[109] T Matsuno S-K Jung Y Matsumoto M Saito and JMorikawa ldquoPreferential cytotoxicity to tumor cells of 35-diprenyl-4-hydroxycinnamic acid (artepillin C) isolated frompropolisrdquo Anticancer Research vol 17 no 5A pp 3565ndash35681997
16 Mediators of Inflammation
[110] X Zhang J-H Zhang X-Y Chen et al ldquoReactive oxy-gen species-induced TXNIP drives fructose-mediated hepaticinflammation and lipid accumulation through NLRP3 inflam-masome activationrdquo Antioxidants and Redox Signaling vol 22no 10 pp 848ndash870 2015
[111] A Zendedel S Johann S Mehrabi et al ldquoActivation and reg-ulation of NLRP3 inflammasome by intrathecal application ofSDF-1a in a spinal cord injury modelrdquoMolecular Neurobiologyvol 53 no 5 pp 3063ndash3075 2016
[112] H Inoue and R Nakata ldquoResveratrol targets in inflammationrdquoEndocrineMetabolic and ImmuneDisordersmdashDrug Targets vol15 no 3 pp 186ndash195 2015
[113] S S Kulkarni and C Canto ldquoThe molecular targets of resver-atrolrdquo Biochimica et Biophysica Acta (BBA)mdashMolecular Basis ofDisease vol 1852 no 6 pp 1114ndash1123 2015
[114] C A Houghton R G Fassett and J S Coombes ldquoSul-foraphane translational research from laboratory bench toclinicrdquo Nutrition Reviews vol 71 no 11 pp 709ndash726 2013
[115] A T Dinkova-Kostova W D Holtzclaw R N Cole et alldquoDirect evidence that sulfhydryl groups of Keap1 are the sensorsregulating induction of phase 2 enzymes that protect againstcarcinogens and oxidantsrdquo Proceedings of the National Academyof Sciences of the United States of America vol 99 no 18 pp11908ndash11913 2002
[116] E Heiss C Herhaus K Klimo H Bartsch and C GerhauserldquoNuclear factor 120581B is a molecular target for sulforaphane-mediated anti-inflammatory mechanismsrdquo The Journal of Bio-logical Chemistry vol 276 no 34 pp 32008ndash32015 2001
[117] A Alfieri S Srivastava R C M Siow et al ldquoSulforaphanepreconditioning of the Nrf2HO-1 defense pathway protectsthe cerebral vasculature against blood-brain barrier disruptionand neurological deficits in strokerdquo Free Radical Biology andMedicine vol 65 pp 1012ndash1022 2013
[118] C Lee G H Park S-R Lee and J-H Jang ldquoAttenuation of120573 -amyloid-induced oxidative cell death by sulforaphane viaactivation of NF-E2-related factor 2rdquo Oxidative Medicine andCellular Longevity vol 2013 Article ID 313510 12 pages 2013
[119] E Barrajon-Catalan M Herranz-Lopez J Joven et al ldquoMolec-ular promiscuity of plant polyphenols in the management ofage-related diseases far beyond their antioxidant propertiesrdquoAdvances in Experimental Medicine and Biology vol 824 pp141ndash159 2014
[120] L Bravo ldquoPolyphenols chemistry dietary sources metabolismand nutritional significancerdquo Nutrition Reviews vol 56 no 11pp 317ndash333 1998
[121] D W Lamming J G Wood and D A Sinclair ldquoSmallmolecules that regulate lifespan evidence for xenohormesisrdquoMolecular Microbiology vol 53 no 4 pp 1003ndash1009 2004
[122] K T Howitz and D A Sinclair ldquoXenohormesis sensing thechemical cues of other speciesrdquo Cell vol 133 no 3 pp 387ndash3912008
[123] P L Hooper P L Hooper M Tytell and L Vıgh ldquoXeno-hormesis health benefits from an eon of plant stress responseevolutionrdquoCell Stress and Chaperones vol 15 no 6 pp 761ndash7702010
[124] B L Queen and T O Tollefsbol ldquoPolyphenols and agingrdquoCurrent Aging Science vol 3 no 1 pp 34ndash42 2010
[125] J A Baur and D A Sinclair ldquoTherapeutic potential of resvera-trol the in vivo evidencerdquo Nature Reviews Drug Discovery vol5 no 6 pp 493ndash506 2006
[126] R A Sharma A J Gescher and W P Steward ldquoCurcumin thestory so farrdquoEuropean Journal of Cancer vol 41 no 13 pp 1955ndash1968 2005
[127] K Milton ldquoMicronutrient intakes of wild primates are humansdifferentrdquo Comparative Biochemistry and Physiology Part AMolecular amp Integrative Physiology vol 136 no 1 pp 47ndash592003
Figure 1 Basic mechanisms of NLRP3 inflammasome activation
2 Mechanism of NLRP3 InflammasomeActivation
NLRP3 inflammasome can be activated by a broad range ofstimuli that belong either to pathogen-associated molecularpatterns (PAMPs) released during viral bacterial fungal orprotozoa infection [10ndash13] or to danger-associated molecularpatterns (DAMPs) of endogenous or exogenous origin likeextracellular ATP reactive oxygen species (ROS) choles-terol monosodium urate (MSU) crystals amyloid beta (A120573)plaques silica or asbestos [14ndash20] (Figure 1)
Due to the multiple functions of IL-1120573 production ofthis cytokine is tightly regulated requiring two signals Thefirst signal called ldquoprimingrdquo is mediated through PAMPsrecognized by specific receptors like TLRs activating signaltransduction pathways that induce the expression of theinflammasome components as well as that of the inactivecytokine precursor pro-IL-1120573 Signaling pathways throughNF120581B p38 and ERK1 have all been associated with theexpression of NLRP3 and pro-IL-1120573 [21ndash23] The secondsignal provided by DAMPs or PAMPs leads to the assemblyof the inflammasome complex that is followed by activationof caspase-1 and the cleavage and secretion of active IL-1120573 [24 25] Considering the diversity of the second signalssensed by NLRP3 it is highly unlikely that NLRP3 is capableof interacting directly with chemically different activatorsIt is more likely that NLRP3 senses a general signal thatinduces the sequential events of inflammasome activationSeveral cellular mechanisms were reported as requirementsfor activation including intracellular release of oxidizedmitochondrial DNA (mtDNA) increased intracellular Ca2+concentration decreased intracellular cAMP level or pore
formation by bacterial toxins [26ndash28] Common cellularevents are assumed to be critical for the inflammasomeactivation including ROS formation potassium (K+) effluxand cathepsin B leakage from lysosomes [29] Howeverdue to the controversial results published in the field theprecise mechanism that mediates NLRP3 inflammasomeactivation is still not known It is conceivable that morethan one single requirement needs to be fulfilled and theserequirements may depend on the activating stimuli also theper se characteristics of the stimulated cell
21 Reactive Oxygen Species Several NLRP3 inflammasomeactivating stimuli like nigericin or ATP induce oxidativestress and the production of intracellular ROS [15] Thesource of ROS is still unclear as some of the studiesreported the role of NADPH oxidase in ROS generation [30]while other studies proved that mitochondrial dysfunctionor ER stress leads to ROS production As a consequenceof mitochondrial dysfunction oxidized mtDNA is releasedwhich can activate NLRP3 inflammasome [26] eventuallyleading to IL-1120573 production It was also shown that incase of increased cytoplasmic ROS reduced thioredoxin(TRX) becomes oxidized and dissociates from thioredoxinbinding protein (TXNIP) that in turn binds to and acti-vates NLRP3 It was also shown that the expression ofTXNIP is upregulated during ER stress which also inducesNLRP3 activation [31] During oxidative stress misfoldedproteins accumulate which are sensed by the ERmembrane-bound inositol-requiring enzyme 1 (IRE1120572) and proteinkinase RNA-like endoplasmic reticulum kinase (PERK)In turn they initiate ER stress response activate NF120581Bpathways and induce the upregulation of TXNIP expres-sion [32] The role of nuclear factor- (rythroid-derived 2)
Mediators of Inflammation 3
like 2 (Nrf2) transcription factor-mediated antioxidant sig-naling pathway has also been reported as a negative regulatorof NLRP3 inflammasome as disruption of Nrf2 leads toincreased production of IL-1120573 [33] Recent works highlightthe importance ofmetabolic changes such as in glycolysis andoxidative phosphorylation that accompany cell activation andinfluence ROS production [34 35]Moreover ROS influencessignal transduction pathways such as NF120581B thus besidesNLRP3 inflammasome activation it is also thought to playa role in the ldquoprimingrdquo step [36]
22 Ion Flux and Perturbation Perturbation of cytosolic ionconcentration such as K+ and Ca2+ is a common resultof several NLRP inflammasome activating stimuli as manyactivators were shown to directly induce ion fluxes Nigericinor the activation of ATP-sensitive P2X7 receptor inducesrapid efflux of K+ [37ndash39] and K+ efflux has been provento act as a common signal to trigger NLRP3 inflammasomeactivation [40] Furthermore several pore forming toxinsresult in an increased intracellular Ca2+ that triggers NLRP3activation [41] Nevertheless changes in intracellular ionconcentration would also stimulate other inflammasomecomplexes which argues against ion flux as the exclusivecause for NLRP3 inflammasome activation
23 Lysosomal Rupture and Cathepsin B Release Destabi-lization of the acidic lysosomal compartment and release oflysosomal protease cathepsin B into the cytoplasm duringphagocytosis of large particles or crystals such as silicaasbestos uric acid or beta-amyloids have also been impli-cated in the activation of the NLRP3 inflammasome [42]Furthermore phagocytosis could also induce K+ effluxAdditionally lysosomes contain high concentration of Ca2+and lysosomal rupture results in the release of Ca2+ intothe cytosol triggering further Ca2+ release from the ERHowever the molecular details and connections of theseevents are not yet clarified In conclusion although NLRP3inflammasome is themost intensively studied inflammasomecomplex it is still unclear which mechanisms are responsiblefor its activation
24 Mitochondrial Dysfunction In response to infection orendogenous stimuli the perturbation of intracellular ROSK+ or lysosomal stability leads to mitochondrial dysfunctionand to the release of mitochondrial DAMPs such as mtDNAcardiolipin or dynamin-related protein 1 (Drp1) [43] Itwas shown that due to increased mtROS level releasedmtDNA is oxidized and activatesNLRP3 inflammasome [26]Cardiolipin is a non-bilayer-forming phospholipid foundin bacteria and in the inner mitochondrial membrane ofeukaryotes and its translocation from the inner membraneto the outer membrane was shown to activate NLRP3 inflam-masomedownstreamofmtROS [44] It was also reported thatGTPaseDrp1 that is needed for the fragmentation and aggre-gation of mitochondria also induces NLRP3 inflammasomeactivation and IL-1120573 secretion in response to VSV infectionbut not to ATP or nigericin [45] Moreover mitofusin anouter mitochondrial GTPase that regulates mitochondrial
fusion was also described as an NLRP3 activator duringviral infection [46] Recently it was described that themitochondrial antiviral signaling protein (MAVS) located inthemitochondrialmembranemediating interferon responsesalso induces NLRP3 inflammasome activation [47] Thesereports demonstrate that the mitochondrion is a complexregulator of cytosolic homeostasis and a central platform forNLRP3 inflammasome activation
25 Autophagy Autophagy is an evolutionarily conservedmechanism to maintain cellular homeostasis by selectivelyeliminating damaged or aging organelles microbes andubiquitinated proteins through the formation of autophago-somes and using lysosomal degradation Lines of evi-dence show that autophagy suppresses organelle stress-induced activation of NLRP3 inflammasome Furthermoreit was reported that inducers of autophagy also inducethe autophagosomal engulfment of IL-1120573 and its lysosomaldegradation [48] It was also shown that damaged mitochon-dria accumulate in autophagy-deficient macrophages that inturn lead to increased intracellular ROS and to the release ofmtDNA [49]
26 Spatial Location of NLRP3 Originally it was shownthat activated NLRP3 inflammasome localizes to the mito-chondria However recently it was described that duringinflammasome activation ER-associated NLRP3 colocalizeswith the mitochondria-associated ASC to the perinuclearspace via a microtubule-mediated organelle transport It wasshown that upon cell activation the decreased intracellularNAD+ level leads to the inhibition of sirtuin 2 (SIRT2)deacetylase resulting in the accumulation of acetylated alfa-tubulin triggering a dynein-dependent transport of mito-chondria to the perinuclear region into the close proximityto the ER [50]
3 NLRP3 Inflammasome and Related Diseases
Understanding the steps and mechanism of NLRP3 inflam-masome activation would be of crucial importance forthe treatment of several diseases in which the inflamma-some complex has been implicated By producing IL-1120573inflammatory cytokine and inducing pyroptosis the primaryfunction of NLRP3 inflammasome is to protect the hostfrom invading microorganisms [78] However nonmicrobialcompounds of either endogenous (self-derived) or exogenous(environmental) origin are also effective inducers of NLRP3inflammasome activation and lead to sterile inflammationallergic responses or other forms of inflammation [79] Forexample studies have shown that NLRP3 may be implicatedin Alzheimerrsquos disease suggesting that misfolded A120573 pro-teins form aggregates that lead to the activation of NLRPinflammasome [80 81] In gout MSU crystals from purinedegradation form deposits in different tissues and specif-ically activate NLRP3 inflammasome [14] Environmentalparticulates such as inhaled asbestos and silica also activateNLRP3 inflammasome and the high concentration of IL-1120573 is involved in the development of asbestosis and silico-sis two progressive pulmonary diseases leading to fibrosis
4 Mediators of Inflammation
[16 82] NLRP3 inflammasome has also been related toallergic responses to a variety of allergens such as aluminumdust mite or ragweed pollen however the molecular detailsof these responses are still not clear [83ndash85]
Other studies associated NLRP3 inflammasome functionwithmetabolic syndrome and type 2 diabetes as NLRP3 defi-cient mice were protected from high fat diet- (HFT-) inducedinflammation glucose intolerance insulin resistance andobesity [86 87]
The dysregulated production of IL-1120573 by the NLRP3inflammasome is the main reason for the development ofCryopyrin-Associated Periodic Syndromes (CAPS) which iscaused by a mutation in NLRP3 gene CAPS is an autoin-flammatory disorder rather than an autoimmune one assymptoms aremediated by the innate immune systemmainlyby monocytes and macrophages that produce huge amountof IL-1120573 Behcetrsquos disease (BD) is another chronic autoin-flammatory disorder of unknown etiology and increasedIL-1120573 production has been noted as a central player in thepathogenesis of this disease Studies demonstrated increasedROS production and consequently increased NLRP3 func-tion in these patients suggesting an important role forNLRP3inflammasome in mediating cytokine production [88] Inaddition to autoinflammatory diseases NLRP3 inflamma-some function has also been implicated in the developmentof autoimmune diseases like rheumatoid arthritis (RA) [89]RA is a common inflammatory disease affecting small jointsand our knowledge about its pathogenesis is still incompleteNevertheless elevated levels of IL-1120573 and high expression ofNLRP3 were detected from the serum and synovial tissue aswell as in macrophages of RA patients [90]
At present the role of NLRP3 inflammasome and IL-1120573 in cancer is highly controversial The microenvironmentof tumors is characterized by an inflammatory milieu thathelps tumor survival with growth hormones endothelialactivation and angiogenesis that leads to metastasis accom-panied by immune suppression IL-1120573 participates in each ofthese mechanisms by stimulating the expression of TNF120572MMPs VEGF ICAM-1 VCAM and so forth Cancer cellslike melanoma or myeloma as well as tumor-associatedmacrophages and dendritic cells were shown to contribute tothe IL-1120573 production that helps survival and growth of tumorcells furthermore excessive production of IL-1120573 can recruitimmunosuppressive cells like myeloid-derived suppressorscells (MDSCs) [91] On the other hand it was also shown thatNLRP3-induced IL-1120573 production boosts T cell function inpatients receiving chemotherapy [92]
The classical medical approach to treating the above-mentioned diseases involves the use of synthetic drugs devel-oped against individual elements of the signaling pathwaythe IL-1120573 cytokine or the IL-1120573 receptor as reviewed inOzaki et al 2015 [93] However today in the health-cautiouslife era the use of botanical and natural compounds hasgained popularity While a few decades ago the use of naturalcompounds was based exclusively on empirical experiencestoday with the highly developed molecular biological highthroughput methods many molecular elements of theiraction have already been identified However fundamentalquestions remain to be answered including bioavailability
effective doses body concentrations cross-reactivity half-life and degradation and synergistic effect of compoundsas well as carefully designed clinical trials The aim of thepresent review is to provide an overview of these plant-derived natural compounds that would support the use ofmedicinal plants (Figure 2) As a variety of compounds caninfluence inflammasome activation and function we havefocused on natural compounds that have been in long termuse in traditional medicine therefore their safety and overalleffect are mostly established However these compoundstypically influence a multitude of pathways and the exactmolecular mechanisms of their beneficial actions are notcompletely clarified (Table 1)
41 Aloe vera Aloe vera is a medical plant used traditionallyin diverse therapeutic applications The gel of Aloe verahas been reported to stimulate wound-healing and skinhydration induce hematopoiesis and possess antidiabeticanticarcinogenic antimicrobial and antioxidant as well asanti-inflammatory activities Over 75 active components havealready been identified in Aloe vera leaf gels [94] andsome of them have been implicated as immunomodulatorycompounds based on animal studies In amouse sepsismodeland in a human colorectal mucosa model treatment withAloe vera significantly inhibited the elevation of TNF120572 IL-6 and IL-1120573 levels [95 96] Studying human THP-1 cellsand human monocyte-derived macrophages it was foundthat Aloe vera treatment significantly reduced LPS-inducedIL-1120573 production [51] Aloe vera inhibited the expressionof pro-IL-1120573 NLRP3 and caspase-1 as well as that of theP2X7 receptor in the LPS-induced primary macrophagesFurthermore LPS-induced activation of signaling pathwayssuch as NF-120581B p38 JNK and ERK were inhibited by Aloevera in these cells [51]
Aloe emodin is an anthraquinone present naturally inAloe leaves It has been shown to promote natural killer cellactivity andmacrophage phagocytosis in tumor [97] Emodinitself appears to have some protective effect in the inflamma-tory response Recently it was shown that emodin attenuatednigericin- ATP- and silica-induced IL-1120573 secretion fromLPS-activated murine bone marrow-derived macrophages(BMDMs) It was also shown that mice treated intraperi-toneally with emodin showed higher survival rates than con-trol mice injected with LPS alone indicating that emodin canameliorate the severity of NLRP3 inflammasome-mediateddisease symptoms in vivo [52] However further moleculardetails of the inhibitory effect are yet to be discovered
42 Curcumin Curcumin is a lipid soluble polyphenol ayellow pigment isolated from the rhizomes of Curcuma longa(turmeric) but also found in other plants like ginger It iswidely used in food coloring and flavoring and it is also addedto cosmetics It has gained attention in recent years for itsmultiple pharmacological properties being antioxidant anti-inflammatory and antimicrobial as well as for its therapeutic
Mediators of Inflammation 5
O
O
OHOH
OH
Emodin
O O
OHHO
Curcumin
O
O
HO
OH
OH
OH
OHQuercetin
O
SN
CS
Sulforaphane
O
OH
OH
HHO
Genipin
O
O
O
OH
OH
OH
HO
OH
OH
OH
EGCG
O
O
O OH
OH
OH
OH
HO
HO
HOMangiferin
OH
OH
OH
OH
OGlc
OGlcGinsenoside
(basic)
OH
OH
OH
HO
OH
HO
Resveratrol
trans- cis-
H3C
H3CO
OCH3
OCH3
CH3
Figure 2 Chemical structure of natural compounds influencing NLRP3 inflammasome activation
potential in cancer autoimmune metabolic pulmonarycardiovascular and neurological diseases (reviewed in [98])
Brain ischemia is known to induce ER stress and inflam-matory responses leading to neuronal damage [99 100] Ina recent study glucose deprivation or hypoxia was reportedto strongly induce the production of glutamate and IL-1120573 inmouse hippocampus [53] It was shown that pretreatmentof the mouse hippocampus with curcumin reduced IL-1120573 production and this effect was attenuated by 51015840-AMP-activated protein kinase (AMPK) inhibitor suggesting thepossible involvement of AMPK The authors also foundthat curcumin attenuated glutamate-induced phosphoryla-tion of PERK and IRE1120572 the transmembrane sensors ofER stress that mediate inflammatory signals Moreoverusing a neuroblastoma cell line they showed that curcumininhibited glutamate-induced ROS generation as well asreduced glutamate-induced TXNIP expression As a possiblemolecular mechanism they found that in mice hippocam-pus glutamate stimulation increased NLRP3 expression andthe cleaved form of caspase-1 enzyme while curcuminattenuated NLRP3 and cleaved caspase-1 expression Theproduction of IL-6 a downstream target of IL-1120573 was alsoinhibited by curcumin treatment In addition curcumineffectively attenuated mitochondrial function and preventedcaspase-3 activation in hippocampus exposed to glutamate
stimulation effectively preventing glutamate-induced cellapoptosis Furthermore in rats curcumin administrationattenuated ischemic brain injury resulting from middlecerebral artery occlusion (MCAO) Based on these findingscurcumin activates AMPK that inhibits glutamate-inducedER stress and ROS production thus inhibiting TXNIP-induced NLRP3 inflammasome activation and ultimatelyreducing IL-1120573 production in mouse hippocampus limitingbrain injury
Macrophages are popular models for the study ofNLRP3 inflammasome activation In another study per-formed on mouse macrophage cell line J774A1 and peri-toneal macrophages curcumin was shown to strongly inhibitIL-1120573 secretion triggered by LPS plus nigericin aluminumATP or MSU [54] Preincubation with curcumin preventednigericin-induced intracellular potassium level decreaseattenuated lysosome damage and cathepsin B leakage andblocked high mobility group box 1 (HMGB-1) release need-less to say all of these are components that may induceNLRP3 inflammasome activation In BMDMs curcumininhibited nigericin- or aluminum crystal-induced ROS pro-duction The authors did not find obvious inhibitory effectof curcumin on JNK and p38 phosphorylation enhancedby nigericin treatment in the LPS-primed macrophageshowever they found that ERK12 phosphorylation was
6 Mediators of Inflammation
Table 1 Natural compounds effecting NLRP3 inflammasome-mediated IL-1 production
Compound Effect Mechanism Target cell Reference
Aloe vera extract Reduced IL-1120573
Reduced expression of NLRP3procaspase-1 and P2X7RInhibition of ERK p38 NF120581Bsignaling
THP-1 and human MF [51]
Aloe emodin Reduced IL-1120573 Reduced expression of NLRP3procaspase-1 and ASC expression BMDM [52]
Aloe emodin Enhanced survival NLRP3-KO mice model of septicshock [52]
Curcumin Reduced IL-1120573 andcaspase-1 inhibition Reduced ER stress through AMPK Mouse hippocampus [53]
Curcumin Reduced ROS and TXNIP expression Neuroblastoma cells [53]
Reduced expression of NLRP3 ASCand caspase-1Reduced ROS and reducedmitochondrial dysfunctionActivation of AMPK and autophagy
Murine hepatocytes [77]
dramatically downregulated In a mouse model of LPS-induced septic shock administration of curcumin signif-icantly decreased ROS level and cathepsin B leakage inperitoneal macrophages additionally peritoneal HMGB-1and IL-1120573 concentrations were downregulated resulting ina reduced LPS-induced splenomegaly These data suggestthat the observed reduction of secreted mature IL-1120573 bycurcumin is primarily attributed to the inhibition of NLRP3inflammasome activation
43 EGCG Epigallocatechin-3-gallate (EGCG) is the majorbioactive polyphenol in green tea that has a well-documentedantioxidant activity as it functions as a free-radical scavengerEGCG was reported to inhibit NF120581B activation and thesubsequent expression of several inflammatory moleculessuch as inducible nitric oxide synthase (iNOS) matrixmetalloproteinases (MMPs) IL-6 and TNF120572 Besides theanti-inflammatory role EGCG was also thought to possessantitumor effect [101]
In unilateral ureteral obstruction mice model renalinflammation has been linked to the activity of NLRP3inflammasome and the overproduction of IL-1120573 Further-more the role of NLRP3 inflammasome was proven in a vari-ety of human nondiabetic and chronic kidney diseases [102]It was reported that EGCG can prevent the development of
lupus nephritis when administered to NZBW F1 mice theclassical model of systemic lupus erythematosus [55] Thesestudies showed that EGCG treatment activated Nrf2 antiox-idant pathway induced the expression of Nrf2 downstreamenzymes like NAD(P)H dehydrogenase (quinone) 1 (NQO1)and heme oxygenase 1 (HO-1) and reduced renal oxidativestress Furthermore EGCG inhibited renal NLRP3 inflam-masome activity and the expressions of NLRP3 caspase-1and IL-1120573 were also reduced possibly due to the EGCG-induced attenuation of NF120581B pathway activity
Very recently the beneficial effect of EGCG was reportedin a contrast-inducednephropathy (CIN) ratmodel [56] CINis a common iatrogenic cause of acute kidney injury (AKI)after exposure to iodinated contrast medium characterizedby oxidative stress and inflammation [103] Similar to theprevious study they found that EGCG treatment reducedoxidative stress and increased Nrf2 and HO-1 expressionThey also found that EGCG reduced the elevated IL-1120573secretion and NLRP3 protein expression The molecularmechanisms of the observed results however were notstudied
44 Genipin Genipin is a water-soluble bifunctional cross-linking reagent that was initially isolated from the Chinesemedicinal plant Gardenia jasminoides (common name jas-mine) and it has been used for centuries as a herbal medicine
8 Mediators of Inflammation
to protect the liver and gallbladder It possesses antihyper-tensive antibleeding and antiswelling properties in additionto exhibiting anti-inflammatory characteristics Chemicallyit is an aglycone derived from an iridoid glycoside calledgeniposide that is enzymatically hydrolyzed to genipin byintestinal bacteria when administered per os [104] Genipinwas reported to inhibit mitochondrial uncoupling protein2 (UCP2) as well as superoxide-activated UCP2-mediatedproton leak occurring in a variety of diseases [105]
Recently it was shown that overexpression of UCP2caused a significant increase in NLRP3 expression in THP-1 cells and this was significantly inhibited by the adminis-tration of genipin while the levels of the adaptor proteinASC did not change [57] Interestingly genipin treatmentattenuated IL-1120573 levels in LPS-primed cells treated with ATPhowever this effect was not observed in cells treated withnigericin In addition it was also shown that inhibition ofATP-mediated inflammasome activation by genipin does notalter the production of other proinflammatory cytokines suchas IL-6 and TNF120572
In another recent study in LPS-primed murine BMDMsgenipin dramatically inhibited IL-1120573 secretion of LPS-primedcells following ATP nigericin MSU crystals or Listeriamonocytogenes treatment [58] Furthermore genipin alsoinhibited the Salmonella typhimurium-induced secretion ofIL-1120573 which is mediated via the activation of NLRC4inflammasome Similar to the previous study LPS-dependentTNF120572 secretion was not impaired by genipin Importantlygenipin treatment did not inhibit the expression of pro-IL-1120573 pro-caspase-1 or ASC proteins however it inhibitedNLRP3-dependent ASC oligomerization in addition to IL-1120573secretion and caspase-1 activation In contrast to its inhibitoryeffect on NLRP3-mediated ASC oligomerization genipindid not affect NLRC4-mediated formation of ASC speckleswhileNLRC4-mediated caspase-1 activationwas significantlydiminished These data indicate that the inhibitory effect ofgenipin on NLRC4 inflammasome activation is independentof ASC
45 Ginseng White ginseng is the naturally dried formof ginseng (Panax ginseng) while red ginseng is made bysteaming and drying fresh ginseng root Red ginseng hasbeen used for centuries as an immune-modulator and hasalso been used as an adjuvant in the treatment of infectiousand metabolic diseases Korean red ginseng contains variousactive components including saponins such as ginsenosidesand nonsaponins such as polysaccharides peptides fattyacids and mineral oils Ginsenosides are the major activecomponents of ginseng They reduce the production ofinflammatory cytokines by inhibiting NF120581B signaling [106]They also have amphiphilic nature and are able to intercalateinto the plasma membrane and influence membrane fluidityand function
It was shown that red ginseng extract (RGE) inhibitedATP- nigericin- and aluminum-induced IL-1120573 secretionin LPS-primed BMDMs and THP-1 cells and amelioratedlethality in LPS-induced septic shock model of mice [59]Furthermore RGE attenuated IL-1120573 secretion in dsDNA-transfected macrophages Similar results were obtained for
ginsenosides Furthermore it was also shown that RGE actedas an inhibitor of both NLRP3 and AIM2 inflammasomeactivations It was also demonstrated that RGE attenuated thesecretion of the active form of caspase-1 (p20)
It was previously reported that endogenousNOproducedby iNOS inhibits NLRP3 inflammasome activation via theS-nitrosylation of NLRP3 protein [107 108] A recent studyreported that ginsenosides negatively regulates LPS-inducedseptic shock in mice by a mechanism involving inhibitionof iNOS expression and the subsequent NO production[60] It was shown that ginsenosides reduced NO leveliNOS expression and ROS level in peritoneal macrophagesand BMDMs after LPS stimulation They also found thatginsenoside treatment attenuated S-nitrosylation of NLRP3protein which resulted in increased IL-beta secretion in LPS-activated macrophages
46 Mangiferin Mangiferin is a water-soluble naturalpolyphenol with a C-glycosylxanthone structure The pri-mary source of mangiferin is the mango tree (Mangiferaindica) however it is also present in some medicinal herbsin Iris unguicularis and in the honeybush a popular herbaltea from South Africa It possesses a wide spectrum ofbeneficial effects on health being used as an analgesicantidiabetic antisclerotic antimicrobial and antiviral as wellas being praised for its anti-inflammatory effects It has beenshown to regulate AMPK activity and in a recent work itwas reported that in human endothelial cells exposed tohigh glucose mangiferin reduced IL-1120573 secretion [61] Fur-thermore mangiferin attenuated IRE1 phosphorylation andreducedROS production and it decreased TXNIP expressionand inhibited ER stress Moreover a decrease in NLRP3expression and IL-1120573 production was also demonstrated
Very recently the protective role of mangiferin wasdescribed in LPS plus D-galactosamine- (D-GalN-) inducedacute liver injury [62] The authors showed that mangiferinreduced IL-1120573 secretion and ROS production and it alsoinhibited iNOS expression but induced Nrf2 and HO-1expression Furthermore it attenuated NLRP3 ASC andcaspase-1 (p10) expression and the subsequent IL-1120573 produc-tion
47 Propolis Propolis is a resinous material produced bybees (Apis mellifera L) through the mixing of secretions andenzymes from their hypopharyngeal glands with the budsof plants and wax A few hundred compounds have beendetected in raw propolis including polyphenols terpenoidssteroids sugar and amino acids Propolis composition islargely influenced by botanical origins and geographicallocation as well as by collection season One of the mostknown biological activities of propolis is related to its anti-inflammatory effect Artepillin C is a simple phenol com-posed of a single ring with two prenyl groups (35-diprenyl-4-hydroxycinnamic acid) and is the major biologically activephenolic ingredient identified in green propolis derived fromSoutheast Brazil [109]
The role of artepillin C was studied on the oxidativemetabolism of PMA-stimulated RAW2647 macrophages[63] It was shown that artepillin C significantly inhibited
Mediators of Inflammation 9
ROS release upon the NLRP3 activator nigericin treatment Itwas also suggested that artepillin C significantly contributedto the modulation of chemokine-mediated inflammation asit significantly downregulated the release of IL-1120573 IL-12p40and TNF120572 by LPS + IFN120574-treated RAW2647 cells whereasthe synthesis of IL-1120572 and IL-6 was not affected Besidesnigericin-mediated IL-1120573 production propolis also inhibitedLegionella pneumophila-induced IL-1120573 cytokine secretionin LPS-primed BMDMs This indicates that both NLRP3and NLRC4 inflammasome functions may be regulated bypropolis however further studies are required to clarify thedetailed molecular mechanism of the observed results
48 Quercetin Quercetin a kind of flavonoid found in avariety of vegetables beverages fruits and herbs exhibitsanti-inflammatory and antioxidant properties Quercetinwasreported to reduce inflammation in visceral adipose tissueprimary human adipocytes and the kidney of fructose-fedrats It was also shown to prevent diabetic kidney injury inratsHowever themechanisms of the action of quercetinwerenot clarified
It has been described that quercetin attenuated fructose-induced hyperuricemia and renal dysfunction In a studyusing streptozotocin- (STZ-) induced diabetic nephropa-thy rat model leading to hyperuricemia and dyslipidemiaquercetin was found to block NLRP3 inflammasome acti-vation [64] It was shown that the STZ-induced expres-sion of inflammasome components was restrained and IL-1120573 secretion was reduced by quercetin treatment Similarresults were obtained studying inflammatory responses infructose-induced hyperuricemia in rat [65] They showedthat fructose significantly elevated the expression of renalNLRP3 ASC and caspase-1 expression while quercetintreatment ameliorated the expression of these proteins Basedon their findings it was suggested that fructose-mediatedrenal NLRP3 inflammasome activation and proinflamma-tory cytokine overproduction may be associated with theimpaired cross talk between renal JAK2-STAT3 and PPAR-120572signaling pathway that in turn regulate renal inflammation
Furthermore it was shown that quercetin markedlyinhibited the overexpression of hepatic TXNIP in additionto reducing the production of ROS and the activation ofNLRP3 inflammasome consequently resulting in decreasedIL-1120573 secretion [66 110]They also showed that the decreasedcaspase-1 activity downregulated the caspase-1-dependentactivation of SREBPs that are involved in fatty acid andcholesterol synthesis They suggested that regulation of theTXNIP-NLRP3-SREBPs pathway by quercetin may partiallymediate the alleviation of hepatic steatosis in these diabeticrats
It was also shown that quercetin treatment regulatedAMPK pathway activation glutamine-glutamate cycle dys-function and TXNIP overexpression moreover it sup-pressed NF120581B pathway eventually leading to impairedNLRP3 inflammasome activation and IL-1120573 production inthe hypothalamus of high fructose- (HF-) fed rats [67]
Using human umbilical vein endothelial cells anothergroup reported that quercetin suppressed palmitate- (PA-) induced IL-1120573 and IL-6 induction [68] Downregulation
of NLRP3 induction was probably partially mediated viathe inhibition of ROS production and TXNIP expressionquercetin also inhibited IKK120573 activation by attenuatingits phosphorylation Furthermore quercetin treatment pro-tected cells against PA insult and significantly reduced thenumber of apoptotic cells Moreover quercetin amelioratedER stress-induced endothelial dysfunction through the acti-vation of AMPK
NLRP3 inflammasome is also recognized to have animportant role in the spinal cord tissue after traumatic spinalcord injury (SCI) and targeting the NLRP3 inflammasomecan inhibit neuroinflammation thereby improving func-tional recovery in SCI rats [111]
Very recently in a ratmodel of SCI quercetin administra-tion was shown to significantly improve functional recovery[69] Histopathological changes of the spinal cord such ascongestion edema neutrophil infiltration and structuraldisruption were inhibited by quercetin administration Toformulate a molecular mechanism the authors showed thatquercetin administration significantly reduced inflammatorycytokine IL-1120573 IL-18 and TNF120572 levels it also reduced theNLRP3 ASC and active caspase-1 protein expression andROS production However further studies are needed tobetter characterize the mechanisms of action underlying thebeneficial effects of quercetin in inflammation and immunity
49 Resveratrol Resveratrol is a polyphenol present inthe skin of grapes and mulberry commonly used in redwine production The beneficial effects of resveratrol arethought to be mediated in part by its antioxidant andanti-inflammatory properties exhibiting beneficial effectsin several diseases [112] Resveratrol exists as two isomerscis- and trans-resveratrol The cis isomer is thought to beproduced naturally during grape fermentation as a resultof isomerization of the trans isomer by yeast isomerasesFurthermore cis-resveratrol can be obtained by exposure ofthe trans isomer to sunlight Several studies have shown thattrans-resveratrol exhibits a wide range of biological activitiesincluding anti-inflammatory antioxidant anticarcinogenicantiaging antiplatelet aggregation immune-modulatory andchemoprevention effects However only few studies havebeen performed to examine the biological effects of the cisisomer Studies on cis-resveratrol have demonstrated thatit also possesses anticancer antimicrobial and antiplateletaggregation activities
One of the biological roles of resveratrol is to initiate theactivation of sirtuin 1 (Sirt1) is a deacetylase that modifies andinactivates inflammatory genes At high doses resveratrolhas been shown to activate AMPK which is involved inthe negative regulation of the NLRP3-inflammasome [113]It was also shown that ionizing radiation-induced IL-1120573secretion by human mesenchymal stem cells (MSCs) aneffect that was effectively abrogated by pretreatment withresveratrol [70] Radiation-induced increase in IL-1120573 occursvia the NLRP3 inflammasome activation however resver-atrol treatment attenuated the expression of NLRP3 It wasalso demonstrated that resveratrol treatment upregulated theexpression of Sirt1 In conclusion it is suggested that Sirt1
10 Mediators of Inflammation
inhibits NF120581B transcriptional activity through deacetylationthat in turn limits the transcription of NLRP3
In another study it was shown that cis-resveratrol pre-treatment significantly inhibited IL-1120573 secretion in THP-1 cellculture supernatants interestingly cis-resveratrol inducedIL-18 secretion under these conditions [71] Accordingly cis-resveratrol significantly reduced IL-1120573 mRNA expressionin contrast cis-resveratrol used at the same concentra-tion increased IL-18 mRNA expression Furthermore cis-resveratrol increased the mRNA and protein levels of NLRP1and NLRP3 indicating that the inhibitory effect of cis-resveratrol on IL-1120573 secretion is not due to the down-regulation of NLRP1 NLRP3 or ASC expression Similarresults were obtained on LPS-primed J774A1 macrophageswhere resveratrol inhibited the ATP-induced IL-1120573 secretionhowever in this study the authors did not find changes in theexpression of NLRP3 [72] showing that the resveratrol didnot inhibit the priming signal of NLRP3
Huang et al suggested that the inhibitory effect of cis-resveratrol on IL-1120573 secretion may be due to the reducedexpression of purinergic receptor P2X7R and the ER stressmarker GRP78 which leads to suppression of ROS pro-duction and reduced caspase-1 and caspase-4 activation Itwas found that cis-resveratrol also inhibited cyclooxygenase-(COX-) 2 expression which may be responsible for theobserved decrease of PGE2 production Furthermore inhi-bition of pro-IL-1120573 and COX-2 expression may occur bydownregulating the activation of the p38 MAPK path-way [71] Importantly in contrast to these observationsincreased phosphorylation of p38 was detected in ATP-activated J774A1 macrophages by Chang et al while itdid not significantly increase the phosphorylation levelsof ERK12 and it reduced the phosphorylation levels ofJNK12 The levels of mtDNA release into the cytosol weresignificantly reduced by resveratrol indicating that therewas less mitochondrial injury in resveratrol-treated cells[72] Furthermore the authors also showed that resveratrolincreased cellular cAMP level in J774A1 macrophages whichacts as a negative regulator of inflammatory responses andinhibits NLRP3 inflammasome activation
The effect of resveratrol on NLRP3 inflammasome wasfurther proved by a study showing that four weeks ofresveratrol administration inhibited the expression of NLRP3inflammasome components IL-1 IL-6 and TNF120572 and inlivers of HF-fed mice [73] They also showed that theregulatory effects of resveratrol on NLRP3 inflammasomemay come about through the combined effects of Sirt1 andSirt6
In a recent study [50] it was found that resveratroltreatment successfully suppressed the maturation of bothIL-1120573 and caspase-1 in response to Pam3CSK4 a TLR12agonist plus various inducers (like nigericin ATP MSUand silica) of the NLRP3-inflammasome In mouse BMDMshowever it did not affect the production of IL-1120573 medi-ated by the NLRC4-inflammasome (flagellin) or the AIM2-inflammasome (dsDNA) On a mouse model of acute goutthey indicated that resveratrol reduced the amount of matureIL-1120573 and the subsequent recruitment of neutrophils intothe peritoneal cavities of mice after challenge with MSU
crystals These findings indicate that resveratrol suppressesthe activation of the NLRP3-inflammasome both in vitroand in vivo As a possible mechanism they showed thatresveratrol at a substantially higher dosage successfullysuppressed mitochondrial ROS production Furthermoreresveratrol treatment prevented the accumulation of acety-lated 120572-tubulin thusinhibiting the proximate localization ofASC and NLRP3 in macrophages
In a very recent publication [74] the authors showed thatresveratrol preventedATP-inducedNLRP3 activation and IL-1120573 production in the BV2 cell line and in septic mice as wellThey also found that resveratrol treatment reduced NLRP3and IL-1120573 expression in the hippocampus of the mice andthey suggested that the protecting effect of resveratrol wasmediated via the increased expression of Sirt1 in BV2 cells
Another recent publication found that glucose-basedperitoneal dialysis increased mitochondrial ROS productionand subsequent IL-1120573 secretion through NLRP3 inflamma-some in human peritoneal mesothelial cells (HPMC) Asa mechanism for its action they showed that resveratrolinduced mitophagyautophagy of the cells via AMPK activa-tion and protected cells fromROS-inducedNLRP3-mediatedinflammatory injury [75]
410 Sulforaphane Sulforaphane (SFN) is a natural com-pound present in cruciferous vegetables such as broccolicabbage Brussel sprouts mustard and radish ChemicallySFN is an isothiocyanate that is known to react withsulfhydryl groups and tomodify proteins at cysteine residuesSulforaphane is produced from the precursor glucoraphaninby the enzymatic activity of myrosinase when the cell wallsof the plant are damaged for example during chewingSFN has been known as a cytoprotective agent for cancerprevention or treatment and it also has an important rolein cardiovascular neurologic and other diseases (reviewedin [114]) SFN is a known inducer of the Nrf2 antioxidantpathway as it activates the Nrf2 transcription factor byreacting with cysteine residues of its repressor Keap1 [115]In addition it also inhibits NF120581B signaling [116]
It was shown that SFN inhibited IL-1120573 processing byNLRP1- NLRP3- NLRC4- and AIM2- inflammasome com-plexes in mouse BMDMs [28] It was also demonstratedthat SFN inhibits the inflammasome in an Nrf2-independentmanner as SFN-mediated inhibition of NLRP3- andNLRC4-dependent IL-1120573 processing and secretion was not reversedin Nrf2-knockout BMDMs When SFN was added directlyto the cell lysates it did not inhibit IL-1120573 processingdemonstrating that SFN does not directly inhibit the proteaseactivity of caspase-1 The authors found that SFN-mediatedinhibition of the inflammasomes is not affected by ROSmodulation and neither proteasome-dependent proteolysisnor de novo protein synthesis is required for SFN-mediatedinhibition of the inflammasomes In a peritonitis model ofacute gout SFN treatment significantly reducedMSU crystal-induced IL-1120573 production demonstrating that SFN inhibitsthe NLRP3 inflammasome function in vivo Nonethelessthe authors concluded that SFN inhibits multiple inflam-masomes in vitro and in vivo by a mechanism independent
Mediators of Inflammation 11
ERKp38
NLRP3
ASCNLRP3
Caspase-1ROS
ER stress
P2X7R ATP
Cathepsin B
TLR
ROS
mtDNA
Sirt2
AcAc
AcAc
AMPK
A
A AC
C
C
Nrf2E
E
UCP2Ge
Ge
Ge
Gi
TXNIPC
NOGi
P
Sirt1R
R
R
R
M
M
M
Q
QQ
SS
S
R
Cardio-lipin
Acetylated 120572-tubulin
Ca2+ influx
IL-1120573
Pro-IL-1120573
K+efflux
120572-Tubulin
Pro-IL-1120573
NF120581B
Figure 3 Molecular targets of natural compounds affecting NLRP3 inflammasome-mediated IL-1 production
of inflammasome priming and Nrf2 signaling however theexact molecular mechanism was not explored
As SFN is able to penetrate the blood-brain barrier[117] it gained a considerable attention as a candidatefor Alzheimerrsquos disease (AD) therapy SFN was shown toprotect the brain from A120573-induced oxidative cell death viaactivation of Nrf2 signaling cascade [118] As A120573 fibrilshave been shown to activate NLRP3 inflammasome thequestion arose whether SFN may regulate this mechanismIn a very recent study it was shown that SFN significantlydownregulated IL-1120573 production and NLRP3 expression inA1205731ndash42 peptide-stimulated human THP-1 cells macrophages[76] It was found that A1205731ndash42 peptide-induced STAT-1phosphorylation was significantly attenuated by SFN Theauthors showed that SFN inducedNrf2 nuclear translocationwhich was subsequently accompanied by an increase in HO-1 protein levels Furthermore A1205731ndash42 peptide-induced IL-1120573 production was diminished by siRNA-mediated knock-down of Nrf2 or HO-1 They also found that the increasedproinflammatory miRNA-146a level following A1205731ndash42 treat-ment was significantly attenuated by SFN whereas miRNA-125b and miRNA-155 levels were not changed These arespecific proinflammatory miRNAs that were reported to beincreased in both the extracellular fluid and cerebrospinalfluid of AD patients In conclusion SFN can suppress A1205731ndash42-induced caspase-1-dependent inflammasome activationpossibly through inhibiting STAT-1 phosphorylation andactivation of the Nrf2HO-1 signaling pathway
Also very recently another research group reported thatoral administrations of SFN suppressed the saturated fattyacid-induced NLRP3 inflammasome activation in the liverof mice [77] They found that SFN decreased the expression
of ASC caspase-1 and IL-1120573 levels additionally it inhibitedthe activity of caspase-1 enzyme in primary hepatocytes Itwas also shown that SFN reduced the palmitate-inducedROS production by the mitochondria implying that SFNprevented mitochondrial dysfunction and this protectingmechanism was in part mediated by the activation of AMPKThey concluded that activation of AMPK and autophagy bySFN could protect from mitochondrial dysfunction inducedby saturated fatty acids resulting in a downregulation of fat-induced activation of the NLRP3 inflammasome
5 NLRP3 Inflammasome and theXenohormesis Hypothesis
As it was described in detail above polyphenols like resvera-trol curcumin EGCG and quercetin are potent inhibitors ofNLRP3 inflammasome-mediated IL-1120573 production typicallyacting at more than one element of the involved pathways(Figure 3)However it should be noted that these polyphenolshave an evenmuch broader biological effect as they influencea variety of pathways [119] though not all are directlyconnected to the function of the NLRP3 inflammasomeImportantly more than 8000 natural polyphenols have beendescribed [120] providing a large library of compounds aspotential inflammasome inhibitors Many of these polyphe-nols (such as resveratrol and curcumin) are overproducedby stressed plants triggering pathways mimicking the effectof caloric restriction It has been proposed that organismsfrom yeast to humans consuming stressed plants couldinterpret the stress signal carried by such polyphenols as apotential risk of future limitation of food availability and in
12 Mediators of Inflammation
turn adapting for the pursuit of longevity a theory termedas Xenohormesis [121ndash123] Interestingly the structurallyunrelated resveratrol and curcumin can achieve this caloricrestriction mimicking effect by activating AMPK and Sirt1[124] However polyphenols are also known to have anantioxidant effect activate glutathione S-transferases andinhibit COX enzymes among many other effects [125 126]Interestingly one of the most frequently used COX inhibitoris aspirin a derivative of another stress-induced phytochem-ical salicylic acid
A major concern of polyphenol use in therapy is thebioavailability of these compounds Nevertheless typicaldietary polyphenol intake is about 14mgkgday which iswithin the range of providing biologically active doses [127]
6 Concluding Remarks
Most of the time inflammasome-mediated IL-1120573 productionor caspase-mediated pyroptosis is beneficial for the host as itprotects from infection or prevents further damageHoweverprolonged cytokine production as in the case of sterileinflammation caused by endogenous danger signals maylead to the development of autoinflammatory or metabolicdiseases Chronic inflammation compromises the hostrsquos lifequality and requires sustained pharmacological and surgicaltreatments The paradigm of drug discovery in Westernmedicine is to develop highly selective compounds againstindividual druggable targets Currently the main treatmentmethods for these patients are targeting IL-1120573 Howeverprolonged usage of drugs may induce different side effectsfurthermore some form of medications are very expensivewhich limits their widespread use
Besides the high expenses another drawback of tradi-tional drug design is that many of the promising compoundsfail in the early or later stages of drug development Tradi-tional medicine uses many plant products to treat diseaseshowever the exact mechanisms behind their use is stillmostly lacking partially as a consequence of the pleiotropiceffect of the active compounds as detailed in this reviewNevertheless clarification of the molecular mechanism ofaction of such natural compounds already used in traditionalmedicine for quite some time will undoubtedly aid in theproduction of safe and cheap candidate medications to beused in the treatment of diseases including those appearingas a consequence of NLRP3 inflammasome-mediated IL-1120573overproduction
Competing Interests
The authors declare no conflict of interests
Acknowledgments
This work was supported by OTKA-K 109429 Szilvia Benkois a receiver of Lajos Szodoray Postdoctoral Fellowship andJanos Bolyai Postdoctoral Fellowship
References
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[2] G Meng F Zhang I Fuss A Kitani and W Strober ldquoA muta-tion in the Nlrp3 gene causing inflammasome hyperactivationpotentiates Th17 cell-dominant immune responsesrdquo Immunityvol 30 no 6 pp 860ndash874 2009
[3] D Lasiglie E Traggiai S Federici et al ldquoRole of IL-1 beta in thedevelopment of human TH17 cells lesson fromNLPR3mutatedpatientsrdquo PLoS ONE vol 6 no 5 Article ID e20014 2011
[4] H Schneider F Pitossi D Balschun A Wagner A Del Reyand H O Besedovsky ldquoA neuromodulatory role of interleukin-1120573 in the hippocampusrdquo Proceedings of the National Academy ofSciences of the United States of America vol 95 no 13 pp 7778ndash7783 1998
[5] E Gabay G Wolf Y Shavit R Yirmiya and M Tal ldquoChronicblockade of interleukin-1 (IL-1) prevents and attenuates neuro-pathic pain behavior and spontaneous ectopic neuronal activityfollowing nerve injuryrdquo European Journal of Pain vol 15 no 3pp 242ndash248 2011
[6] A del Rey A V Apkarian M Martina and H O BesedovskyldquoChronic neuropathic pain-like behavior and brain-borne IL-1120573rdquo Annals of the New York Academy of Sciences vol 1262 no 1pp 101ndash107 2012
[7] R Yirmiya and I Goshen ldquoImmune modulation of learningmemory neural plasticity and neurogenesisrdquo Brain Behaviorand Immunity vol 25 no 2 pp 181ndash213 2011
[8] M R de Zoete N W Palm S Zhu and R A FlavellldquoInflammasomesrdquo Cold Spring Harbor Perspectives in Biologyvol 6 no 12 Article ID a016287 2014
[9] M Dagenais A Skeldon and M Saleh ldquoThe inflammasomein memory of Dr Jurg Tschopprdquo Cell Death and Differentiationvol 19 no 1 pp 5ndash12 2012
[10] T-D Kanneganti N OzorenM Body-Malapel et al ldquoBacterialRNA and small antiviral compounds activate caspase-1 throughcryopyrinNalp3rdquoNature vol 440 no 7081 pp 233ndash236 2006
[11] S Mariathasan D S Weiss K Newton et al ldquoCryopyrinactivates the inflammasome in response to toxins and ATPrdquoNature vol 440 no 7081 pp 228ndash232 2006
[12] A G Hise J Tomalka S Ganesan et al ldquoAn essential role forthe NLRP3 inflammasome in host defense against the humanfungal pathogen candida albicansrdquo Cell Host and Microbe vol5 no 5 pp 487ndash497 2009
[13] M T Shio S C Eisenbarth M Savaria et al ldquoMalarialhemozoin activates theNLRP3 inflammasome through Lyn andSyk kinasesrdquo PLoS Pathogens vol 5 no 8 article e10005592009
[14] F Martinon V Petrilli A Mayor A Tardivel and J TschoppldquoGout-associated uric acid crystals activate the NALP3 inflam-masomerdquo Nature vol 440 no 7081 pp 237ndash241 2006
[15] J Tschopp and K Schroder ldquoNLRP3 inflammasome activationthe convergence of multiple signalling pathways on ROS pro-ductionrdquo Nature Reviews Immunology vol 10 no 3 pp 210ndash215 2010
[16] C Dostert V Petrilli R Van Bruggen C Steele B TMossmanand J Tschopp ldquoInnate immune activation through Nalp3inflammasome sensing of asbestos and silicardquo Science vol 320no 5876 pp 674ndash677 2008
Mediators of Inflammation 13
[17] A Halle V Hornung G C Petzold et al ldquoThe NALP3inflammasome is involved in the innate immune response toamyloid-120573rdquoNature Immunology vol 9 no 8 pp 857ndash865 2008
[18] B Pazar H-K Ea S Narayan et al ldquoBasic calcium phosphatecrystals induce monocytemacrophage IL-1120573 secretion throughthe NLRP3 inflammasome in vitrordquo Journal of Immunology vol186 no 4 pp 2495ndash2502 2011
[19] P Duewell H Kono K J Rayner et al ldquoNLRP3 inflammasomesare required for atherogenesis and activated by cholesterolcrystalsrdquo Nature vol 464 no 7293 pp 1357ndash1361 2010
[20] S Benko D J Philpott and S E Girardin ldquoThe microbial anddanger signals that activate Nod-like receptorsrdquo Cytokine vol43 no 3 pp 368ndash373 2008
[21] F G Bauernfeind G Horvath A Stutz et al ldquoCutting edgeNF-120581B activating pattern recognition and cytokine receptorslicense NLRP3 inflammasome activation by regulating NLRP3expressionrdquo Journal of Immunology vol 183 no 2 pp 787ndash7912009
[22] M G Ghonime O R Shamaa S Das et al ldquoInflammasomepriming by lipopolysaccharide is dependent upon ERK signal-ing and proteasome functionrdquo Journal of Immunology vol 192no 8 pp 3881ndash3888 2014
[23] Q He H You X-M Li T-H Liu P Wang and B-E WangldquoHMGB1 promotes the synthesis of pro-il-1120573 and pro-il-18by activation of p38 MAPK and NF-kB through receptorsfor advanced glycation end-products in macrophagesrdquo AsianPacific Journal of Cancer Prevention vol 13 no 4 pp 1365ndash13702012
[24] C Jin and R A Flavell ldquoMolecular mechanism of NLRP3inflammasome activationrdquo Journal of Clinical Immunology vol30 no 5 pp 628ndash631 2010
[25] S MMan and T-D Kanneganti ldquoRegulation of inflammasomeactivationrdquo Immunological Reviews vol 265 no 1 pp 6ndash212015
[26] K Shimada T R Crother J Karlin et al ldquoOxidized mito-chondrial DNA activates the NLRP3 inflammasome duringapoptosisrdquo Immunity vol 36 no 3 pp 401ndash414 2012
[27] G-S Lee N Subramanian A I Kim et al ldquoThe calcium-sensing receptor regulates the NLRP3 inflammasome throughCa2+ and cAMPrdquo Nature vol 491 no 7427 pp 123ndash127 2012
[28] A J Greaney SH Leppla andMMoayeri ldquoBacterial exotoxinsand the inflammasomerdquo Frontiers in Immunology vol 6 article570 2015
[29] E I Elliott and F S Sutterwala ldquoInitiation and perpetuation ofNLRP3 inflammasome activation and assemblyrdquo ImmunologicalReviews vol 265 no 1 pp 35ndash52 2015
[30] A Sokolovska C E Becker W K E Ip et al ldquoActiva-tion of caspase-1 by the NLRP3 inflammasome regulates theNADPHoxidaseNOX2 to control phagosome functionrdquoNatureImmunology vol 14 no 6 pp 543ndash553 2013
[31] S Kim Y Joe S O Jeong et al ldquoEndoplasmic reticulum stressis sufficient for the induction of IL-1120573 production via activationof the NF-120581B and inflammasome pathwaysrdquo Innate Immunityvol 20 no 8 pp 799ndash815 2014
[32] A G Lerner J-P Upton P V K Praveen et al ldquoIRE1120572induces thioredoxin-interacting protein to activate the NLRP3inflammasome and promote programmed cell death underirremediable ER stressrdquo Cell Metabolism vol 16 no 2 pp 250ndash264 2012
[33] S Freigang F Ampenberger G Spohn et al ldquoNrf2 is essentialfor cholesterol crystal-induced inflammasome activation and
exacerbation of atherosclerosisrdquo European Journal of Immunol-ogy vol 41 no 7 pp 2040ndash2051 2011
[34] G M Tannahill and L A J OrsquoNeill ldquoThe emerging role ofmetabolic regulation in the functioning of Toll-like receptorsand the NOD-like receptor Nlrp3rdquo FEBS Letters vol 585 no11 pp 1568ndash1572 2011
[35] M Haneklaus and L A J OrsquoNeill ldquoNLRP3 at the interfaceof metabolism and inflammationrdquo Immunological Reviews vol265 no 1 pp 53ndash62 2015
[36] F Bauernfeind E Bartok A Rieger L Franchi G Nunez andV Hornung ldquoCutting edge reactive oxygen species inhibitorsblock priming but not activation of the NLRP3 inflamma-somerdquo The Journal of Immunology vol 187 no 2 pp 613ndash6172011
[37] D Perregaux and C A Gabel ldquoInterleukin-1 beta maturationand release in response to ATP and nigericin Evidence thatpotassium depletion mediated by these agents is a necessaryand common feature of their activityrdquoThe Journal of BiologicalChemistry vol 269 no 21 pp 15195ndash15203 1994
[38] J M Kahlenberg K C Lundberg S B Kertesy Y Qu and GR Dubyak ldquoPotentiation of caspase-1 activation by the P2X7receptor is dependent on TLR signals and requires NF-120581B-driven protein synthesisrdquo Journal of Immunology vol 175 no11 pp 7611ndash7622 2005
[39] R Munoz-Planillo P Kuffa G Martınez-Colon B Smith TRajendiran and G Nunez ldquoK+ efflux is the common triggerof NLRP3 inflammasome activation by bacterial toxins andparticulate matterrdquo Immunity vol 38 no 6 pp 1142ndash1153 2013
[40] V Petrilli S Papin C Dostert A Mayor F Martinon and JTschopp ldquoActivation of the NALP3 inflammasome is triggeredby low intracellular potassium concentrationrdquo Cell Death andDifferentiation vol 14 no 9 pp 1583ndash1589 2007
[41] T Murakami J Ockinger J Yu et al ldquoCritical role for calciummobilization in activation of the NLRP3 inflammasomerdquo Pro-ceedings of the National Academy of Sciences of the United Statesof America vol 109 no 28 pp 11282ndash11287 2012
[42] V Hornung F Bauernfeind A Halle et al ldquoSilica crystals andaluminum salts activate the NALP3 inflammasome throughphagosomal destabilizationrdquo Nature Immunology vol 9 no 8pp 847ndash856 2008
[43] J Dan Dunn L A J Alvarez X Zhang and T SoldatildquoReactive oxygen species and mitochondria a nexus of cellularhomeostasisrdquo Redox Biology vol 6 pp 472ndash485 2015
[44] S S Iyer Q He J R Janczy et al ldquoMitochondrial cardiolipinis required for Nlrp3 inflammasome activationrdquo Immunity vol39 no 2 pp 311ndash323 2013
[45] X Wang W Jiang Y Yan et al ldquoRNA viruses promoteactivation of the NLRP3 inflammasome through a RIP1-RIP3-DRP1 signaling pathwayrdquoNature Immunology vol 15 no 12 pp1126ndash1133 2014
[46] T Ichinohe T Yamazaki T Koshiba and Y Yanagi ldquoMitochon-drial protein mitofusin 2 is required for NLRP3 inflammasomeactivation afterRNAvirus infectionrdquoProceedings of theNationalAcademy of Sciences of the United States of America vol 110 no44 pp 17963ndash17968 2013
[47] N Subramanian K Natarajan M R Clatworthy Z Wangand R N Germain ldquoThe adaptor MAVS promotes NLRP3mitochondrial localization and inflammasome activationrdquo Cellvol 153 no 2 pp 348ndash361 2013
[48] S Y Shaw K Tran A B Castoreno et al ldquoSelective modulationof autophagy innate immunity and adaptive immunity by small
14 Mediators of Inflammation
moleculesrdquo ACS Chemical Biology vol 8 no 12 pp 2724ndash27332013
[49] K Nakahira J A Haspel V A K Rathinam et al ldquoAutophagyproteins regulate innate immune responses by inhibiting therelease of mitochondrial DNA mediated by the NALP3 inflam-masomerdquo Nature Immunology vol 12 no 3 pp 222ndash230 2011
[50] T Misawa M Takahama T Kozaki et al ldquoMicrotubule-drivenspatial arrangement ofmitochondria promotes activation of theNLRP3 inflammasomerdquo Nature Immunology vol 14 no 5 pp454ndash460 2013
[51] M M Budai A Varga S Milesz J Tozser and S BenkoldquoAloe vera downregulates LPS-induced inflammatory cytokineproduction and expression of NLRP3 inflammasome in humanmacrophagesrdquo Molecular Immunology vol 56 no 4 pp 471ndash479 2013
[52] J-W Han D-W Shim W-Y Shin et al ldquoAnti-inflammatoryeffect of emodin via attenuation of NLRP3 inflammasomeactivationrdquo International Journal of Molecular Sciences vol 16no 4 pp 8102ndash8109 2015
[53] Y Li J Li S Li et al ldquoCurcumin attenuates glutamate neurotox-icity in the hippocampus by suppression of ER stress-associatedTXNIPNLRP3 inflammasome activation in a manner depen-dent onAMPKrdquoToxicology andApplied Pharmacology vol 286no 1 pp 53ndash63 2015
[54] Z Gong J Zhou H Li et al ldquoCurcumin suppresses NLRP3inflammasome activation and protects against LPS-inducedseptic shockrdquo Molecular Nutrition and Food Research vol 59no 11 pp 2132ndash2142 2015
[55] P-Y Tsai S-M Ka J-M Chang et al ldquoEpigallocatechin-3-gallate prevents lupus nephritis development in mice viaenhancing the Nrf2 antioxidant pathway and inhibiting NLRP3inflammasome activationrdquo Free Radical Biology and Medicinevol 51 no 3 pp 744ndash754 2011
[56] Z Gao Y Han Y Hu et al ldquoTargeting HO-1 byepigallocatechin-3-gallate reduces contrast-induced renalinjury via anti-oxidative stress and anti-inflammationpathwaysrdquo PLOS ONE vol 11 no 2 article e0149032 2016
[57] V Rajanbabu L Galam J Fukumoto et al ldquoGenipin suppressesNLRP3 inflammasome activation through uncoupling protein-2rdquo Cellular Immunology vol 297 no 1 pp 40ndash45 2015
[58] S-X Yu C-T DuW Chen et al ldquoGenipin inhibits NLRP3 andNLRC4 inflammasome activation via autophagy suppressionrdquoScientific Reports vol 5 article 17935 2015
[59] J Kim H Ahn B-C Han et al ldquoKorean red ginseng extractsinhibit NLRP3 and AIM2 inflammasome activationrdquo Immunol-ogy Letters vol 158 no 1-2 pp 143ndash150 2014
[60] S-J Yoon J-Y Park S Choi et al ldquoGinsenoside Rg3 regulatesS-nitrosylation of the NLRP3 inflammasome via suppression ofiNOSrdquo Biochemical and Biophysical Research Communicationsvol 463 no 4 pp 1184ndash1189 2015
[61] J Song J Li F Hou X Wang and B Liu ldquoMangiferininhibits endoplasmic reticulum stress-associated thioredoxin-interacting proteinNLRP3 inflammasome activation with reg-ulation of AMPK in endothelial cellsrdquo Metabolism vol 64 no3 pp 428ndash437 2015
[62] C-W Pan Z-Z Pan J-J Hu et al ldquoMangiferin alleviateslipopolysaccharide and D-galactosamine-induced acute liverinjury by activating the Nrf2 pathway and inhibiting NLRP3inflammasome activationrdquo European Journal of Pharmacologyvol 770 pp 85ndash91 2016
[63] J I Hori D S Zamboni D B Carrao GHGoldman andAABerretta ldquoThe inhibition of inflammasome by Brazilian propo-lis (EPP-AF)rdquo Evidence-Based Complementary and AlternativeMedicine vol 2013 Article ID 418508 11 pages 2013
[64] C Wang Y Pan Q-Y Zhang F-M Wang and L-D KongldquoQuercetin and allopurinol ameliorate kidney injury in STZ-treated rats with regulation of renal NLRP3 inflammasomeactivation and lipid accumulationrdquo PLoS ONE vol 7 no 6Article ID e38285 2012
[65] Q-H Hu X Zhang Y Pan Y-C Li and L-D Kong ldquoAllop-urinol quercetin and rutin ameliorate renal NLRP3 inflamma-some activation and lipid accumulation in fructose-fed ratsrdquoBiochemical Pharmacology vol 84 no 1 pp 113ndash125 2012
[66] WWangCWangX-QDing et al ldquoQuercetin and allopurinolreduce liver thioredoxin-interacting protein to alleviate inflam-mation and lipid accumulation in diabetic ratsrdquo British Journalof Pharmacology vol 169 no 6 pp 1352ndash1371 2013
[67] Q-Y Zhang Y Pan R Wang et al ldquoQuercetin inhibitsAMPKTXNIP activation and reduces inflammatory lesions toimprove insulin signaling defect in the hypothalamus of highfructose-fed ratsrdquo Journal of Nutritional Biochemistry vol 25no 4 pp 420ndash428 2014
[68] J Wu X Xu Y Li et al ldquoQuercetin luteolin and epigallo-catechin gallate alleviate TXNIP and NLRP3-mediated inflam-mation and apoptosis with regulation of AMPK in endothelialcellsrdquo European Journal of Pharmacology vol 745 pp 59ndash682015
[69] W Jiang Y Huang N Han et al ldquoQuercetin suppresses NLRP3inflammasome activation and attenuates histopathology in a ratmodel of spinal cord injuryrdquo Spinal Cord vol 54 pp 592ndash5962016
[70] Y Fu Y Wang L Du et al ldquoResveratrol inhibits ionisingirradiation-induced inflammation in MSCs by activating Sirt1and limiting NLRP-3 inflammasome activationrdquo InternationalJournal ofMolecular Sciences vol 14 no 7 pp 14105ndash14118 2013
[71] T-T Huang H-C Lai Y-B Chen et al ldquoCis-Resveratrolproduces anti-inflammatory effects by inhibiting canonicaland non-canonical inflammasomes in macrophagesrdquo InnateImmunity vol 20 no 7 pp 735ndash750 2014
[72] Y-P Chang S-M Ka W-H Hsu et al ldquoResveratrol inhibitsNLRP3 inflammasome activation by preserving mitochondrialintegrity and augmenting autophagyrdquo Journal of Cellular Physi-ology vol 230 no 7 pp 1567ndash1579 2015
[73] S J Yang and Y Lim ldquoResveratrol ameliorates hepaticmetaflammation and inhibits NLRP3 inflammasome activa-tionrdquoMetabolism vol 63 no 5 pp 693ndash701 2014
[74] D-M Sui Q Xie W-J Yi et al ldquoResveratrol protects againstsepsis-associated encephalopathy and inhibits the NLRP3IL-1 120573 axis in microgliardquo Mediators of Inflammation vol 2016Article ID 1045657 10 pages 2016
[75] J Wu X Li G Zhu Y Zhang M He and J Zhang ldquoTherole of Resveratrol-inducedmitophagyautophagy in peritonealmesothelial cells inflammatory injury via NLRP3 inflamma-some activation triggered bymitochondrial ROSrdquoExperimentalCell Research vol 341 no 1 pp 42ndash53 2016
[76] Y W An K A Jhang S Y Woo J L Kang and Y HChong ldquoSulforaphane exerts its anti-inflammatory effectagainst amyloid-120573 peptide via STAT-1 dephosphorylationand activation of Nrf2HO-1 cascade in human THP-1macrophagesrdquo Neurobiology of Aging vol 38 pp 1ndash10 2016
[77] G Yang H E Lee and J Y Lee ldquoA pharmacological inhibitorof NLRP3 inflammasome prevents non-alcoholic fatty liver
Mediators of Inflammation 15
disease in a mouse model induced by high fat dietrdquo ScientificReports vol 6 Article ID 24399 2016
[78] L Franchi R Munoz-Planillo and G Nunez ldquoSensing andreacting to microbes through the inflammasomesrdquo NatureImmunology vol 13 no 4 pp 325ndash332 2012
[79] S L Cassel and F S Sutterwala ldquoSterile inflammatory responsesmediated by the NLRP3 inflammasomerdquo European Journal ofImmunology vol 40 no 3 pp 607ndash611 2010
[80] M-S Tan J-T Yu T Jiang X-C Zhu and L Tan ldquoThe NLRP3inflammasome in alzheimerrsquos diseaserdquoMolecular Neurobiologyvol 48 no 3 pp 875ndash882 2013
[81] M Gold and J El Khoury ldquo120573-amyloid microglia andthe inflammasome in Alzheimerrsquos diseaserdquo Seminars inImmunopathology vol 37 no 6 pp 607ndash611 2015
[82] P M Peeters T N Perkins E F M Wouters B T Mossmanand N L Reynaert ldquoSilica induces NLRP3 inflammasomeactivation in human lung epithelial cellsrdquo Particle and FibreToxicology vol 10 no 1 article 3 2013
[83] H Watanabe O Gaide V Petrilli et al ldquoActivation of the IL-1120573-processing inflammasome is involved in contact hypersen-sitivityrdquo Journal of Investigative Dermatology vol 127 no 8 pp1956ndash1963 2007
[84] X Dai K Sayama M Tohyama et al ldquoMite allergen is adanger signal for the skin via activation of inflammasome inkeratinocytesrdquo Journal of Allergy and Clinical Immunology vol127 no 3 pp 806ndash814 2011
[85] A Varga M M Budai S Milesz A Bacsi J Tozser and SBenko ldquoRagweed pollen extract intensifies lipopolysaccharide-induced priming of NLRP3 inflammasome in humanmacrophagesrdquo Immunology vol 138 no 4 pp 392ndash4012013
[86] B Vandanmagsar Y-H Youm A Ravussin et al ldquoThe NLRP3inflammasome instigates obesity-induced inflammation andinsulin resistancerdquo Nature Medicine vol 17 no 2 pp 179ndash1892011
[87] H Wen D Gris Y Lei et al ldquoFatty acid-induced NLRP3-ASCinflammasome activation interferes with insulin signalingrdquoNature Immunology vol 12 no 5 pp 408ndash415 2011
[88] L Liang X Tan Q Zhou et al ldquoIL-1120573 triggered by pepti-doglycan and lipopolysaccharide through TLR24 and ROS-NLRP3 inflammasome- dependent pathways is involved inocular behcetrsquos diseaserdquo Investigative Ophthalmology and VisualScience vol 54 no 1 pp 402ndash414 2013
[89] S Rosengren H M Hoffman W Bugbee and D L BoyleldquoExpression and regulation of cryopyrin and related proteinsin rheumatoid arthritis synoviumrdquo Annals of the RheumaticDiseases vol 64 no 5 pp 708ndash714 2005
[90] J M Kahlenberg ldquoAnti-inflammatory panaceaThe expandingtherapeutics of interleukin-1 blockaderdquo Current Opinion inRheumatology vol 28 no 3 pp 197ndash203 2016
[91] C-H Chien M-J Lee H-C Liou H-H Liou and W-MFu ldquoLocal immunosuppressive microenvironment enhancesmigration of melanoma cells to lungs in DJ-1 knockout micerdquoPLoS ONE vol 10 no 2 Article ID e0115827 2015
[92] C Antonopoulos and G R Dubyak ldquoChemotherapy engagesmultiple pathways leading to IL-1120573 production by myeloidleukocytesrdquo OncoImmunology vol 3 no 1 Article ID e274992014
[93] E Ozaki M Campbell and S L Doyle ldquoTargeting the NLRP3inflammasome in chronic inflammatory diseases current per-spectivesrdquo Journal of Inflammation Research vol 8 pp 15ndash272015
[94] J H Hamman ldquoComposition and applications of Aloe vera leafgelrdquoMolecules vol 13 no 8 pp 1599ndash1616 2008
[95] L Langmead R J Makins and D S Rampton ldquoAnti-inflammatory effects of aloe vera gel in human colorectalmucosa in vitrordquo Alimentary Pharmacology and Therapeuticsvol 19 no 5 pp 521ndash527 2004
[96] N Yun C-H Lee and S-M Lee ldquoProtective effect of Aloe veraon polymicrobial sepsis inmicerdquo Food andChemical Toxicologyvol 47 no 6 pp 1341ndash1348 2009
[97] C S Yu F S Yu J K Chan et al ldquoAloe-emodin affects the levelsof cytokines and functions of leukocytes from Sprague-Dawleyratsrdquo In Vivo vol 20 no 4 pp 505ndash509 2006
[98] M Pulido-Moran J Moreno-Fernandez C Ramirez-Tortosaand M Ramirez-Tortosa ldquoCurcumin and healthrdquo Moleculesvol 21 no 3 article E264 2016
[99] Y-F Dong L-X Wang X Huang et al ldquoKir61 knock-down aggravates cerebral ischemiareperfusion-induced neuralinjury in micerdquo CNS Neuroscience and Therapeutics vol 19 no8 pp 617ndash624 2013
[100] P J Maier K Zemoura M A Acuna G E Yevenes HU Zeilhofer and D Benke ldquoIschemia-like oxygen and glu-cose deprivation mediates down-regulation of cell surface 120574-aminobutyric acidB receptors via the endoplasmic reticulum(ER) stress-induced transcription factor CCAATenhancer-binding protein (CEBP)-homologous protein (CHOP)rdquo TheJournal of Biological Chemistry vol 289 no 18 pp 12896ndash129072014
[101] H-Y Shin S-H Kim H-J Jeong et al ldquoEpigallocatechin-3-gallate inhibits secretion of TNF-120572 IL-6 and IL-8 through theattenuation of ERK and NF-120581B in HMC-1 cellsrdquo InternationalArchives of Allergy and Immunology vol 142 no 4 pp 335ndash3442007
[102] W P Pulskens L M Butter G J Teske et al ldquoNlrp3 preventsearly renal interstitial edema and vascular permeability inunilateral ureteral obstructionrdquo PLoS ONE vol 9 no 1 ArticleID e85775 2014
[103] S Kamath and C A Roobottom ldquoHyperdense pericardial effu-sion in dermatomyositis and contrast induced nephropathyrdquoEmergency Radiology vol 11 no 3 pp 177ndash179 2005
[104] T Akao K Kobashi and M Aburada ldquoEnzymic studies onthe animal and intestinal bacterial metabolism of geniposiderdquoBiological and Pharmaceutical Bulletin vol 17 no 12 pp 1573ndash1576 1994
[105] R Wang K C MoYung M H Zhang and K Poon ldquoUCP2-and non-UCP2-mediated electric current in eukaryotic cellsexhibits different propertiesrdquo Environmental Science and Pollu-tion Research vol 22 no 24 pp 19618ndash19631 2015
[106] J-M Lu Q Yao and C Chen ldquoGinseng compounds an updateon their molecular mechanisms and medical applicationsrdquoCurrent Vascular Pharmacology vol 7 no 3 pp 293ndash302 2009
[107] E Hernandez-Cuellar K Tsuchiya H Hara et al ldquoCuttingedge nitric oxide inhibits the NLRP3 inflammasomerdquo TheJournal of Immunology vol 189 no 11 pp 5113ndash5117 2012
[108] B B Mishra V A K Rathinam G W Martens et alldquoNitric oxide controls the immunopathology of tuberculosis byinhibiting NLRP3 inflammasome-dependent processing of IL-1120573rdquo Nature Immunology vol 14 no 1 pp 52ndash60 2013
[109] T Matsuno S-K Jung Y Matsumoto M Saito and JMorikawa ldquoPreferential cytotoxicity to tumor cells of 35-diprenyl-4-hydroxycinnamic acid (artepillin C) isolated frompropolisrdquo Anticancer Research vol 17 no 5A pp 3565ndash35681997
16 Mediators of Inflammation
[110] X Zhang J-H Zhang X-Y Chen et al ldquoReactive oxy-gen species-induced TXNIP drives fructose-mediated hepaticinflammation and lipid accumulation through NLRP3 inflam-masome activationrdquo Antioxidants and Redox Signaling vol 22no 10 pp 848ndash870 2015
[111] A Zendedel S Johann S Mehrabi et al ldquoActivation and reg-ulation of NLRP3 inflammasome by intrathecal application ofSDF-1a in a spinal cord injury modelrdquoMolecular Neurobiologyvol 53 no 5 pp 3063ndash3075 2016
[112] H Inoue and R Nakata ldquoResveratrol targets in inflammationrdquoEndocrineMetabolic and ImmuneDisordersmdashDrug Targets vol15 no 3 pp 186ndash195 2015
[113] S S Kulkarni and C Canto ldquoThe molecular targets of resver-atrolrdquo Biochimica et Biophysica Acta (BBA)mdashMolecular Basis ofDisease vol 1852 no 6 pp 1114ndash1123 2015
[114] C A Houghton R G Fassett and J S Coombes ldquoSul-foraphane translational research from laboratory bench toclinicrdquo Nutrition Reviews vol 71 no 11 pp 709ndash726 2013
[115] A T Dinkova-Kostova W D Holtzclaw R N Cole et alldquoDirect evidence that sulfhydryl groups of Keap1 are the sensorsregulating induction of phase 2 enzymes that protect againstcarcinogens and oxidantsrdquo Proceedings of the National Academyof Sciences of the United States of America vol 99 no 18 pp11908ndash11913 2002
[116] E Heiss C Herhaus K Klimo H Bartsch and C GerhauserldquoNuclear factor 120581B is a molecular target for sulforaphane-mediated anti-inflammatory mechanismsrdquo The Journal of Bio-logical Chemistry vol 276 no 34 pp 32008ndash32015 2001
[117] A Alfieri S Srivastava R C M Siow et al ldquoSulforaphanepreconditioning of the Nrf2HO-1 defense pathway protectsthe cerebral vasculature against blood-brain barrier disruptionand neurological deficits in strokerdquo Free Radical Biology andMedicine vol 65 pp 1012ndash1022 2013
[118] C Lee G H Park S-R Lee and J-H Jang ldquoAttenuation of120573 -amyloid-induced oxidative cell death by sulforaphane viaactivation of NF-E2-related factor 2rdquo Oxidative Medicine andCellular Longevity vol 2013 Article ID 313510 12 pages 2013
[119] E Barrajon-Catalan M Herranz-Lopez J Joven et al ldquoMolec-ular promiscuity of plant polyphenols in the management ofage-related diseases far beyond their antioxidant propertiesrdquoAdvances in Experimental Medicine and Biology vol 824 pp141ndash159 2014
[120] L Bravo ldquoPolyphenols chemistry dietary sources metabolismand nutritional significancerdquo Nutrition Reviews vol 56 no 11pp 317ndash333 1998
[121] D W Lamming J G Wood and D A Sinclair ldquoSmallmolecules that regulate lifespan evidence for xenohormesisrdquoMolecular Microbiology vol 53 no 4 pp 1003ndash1009 2004
[122] K T Howitz and D A Sinclair ldquoXenohormesis sensing thechemical cues of other speciesrdquo Cell vol 133 no 3 pp 387ndash3912008
[123] P L Hooper P L Hooper M Tytell and L Vıgh ldquoXeno-hormesis health benefits from an eon of plant stress responseevolutionrdquoCell Stress and Chaperones vol 15 no 6 pp 761ndash7702010
[124] B L Queen and T O Tollefsbol ldquoPolyphenols and agingrdquoCurrent Aging Science vol 3 no 1 pp 34ndash42 2010
[125] J A Baur and D A Sinclair ldquoTherapeutic potential of resvera-trol the in vivo evidencerdquo Nature Reviews Drug Discovery vol5 no 6 pp 493ndash506 2006
[126] R A Sharma A J Gescher and W P Steward ldquoCurcumin thestory so farrdquoEuropean Journal of Cancer vol 41 no 13 pp 1955ndash1968 2005
[127] K Milton ldquoMicronutrient intakes of wild primates are humansdifferentrdquo Comparative Biochemistry and Physiology Part AMolecular amp Integrative Physiology vol 136 no 1 pp 47ndash592003
like 2 (Nrf2) transcription factor-mediated antioxidant sig-naling pathway has also been reported as a negative regulatorof NLRP3 inflammasome as disruption of Nrf2 leads toincreased production of IL-1120573 [33] Recent works highlightthe importance ofmetabolic changes such as in glycolysis andoxidative phosphorylation that accompany cell activation andinfluence ROS production [34 35]Moreover ROS influencessignal transduction pathways such as NF120581B thus besidesNLRP3 inflammasome activation it is also thought to playa role in the ldquoprimingrdquo step [36]
22 Ion Flux and Perturbation Perturbation of cytosolic ionconcentration such as K+ and Ca2+ is a common resultof several NLRP inflammasome activating stimuli as manyactivators were shown to directly induce ion fluxes Nigericinor the activation of ATP-sensitive P2X7 receptor inducesrapid efflux of K+ [37ndash39] and K+ efflux has been provento act as a common signal to trigger NLRP3 inflammasomeactivation [40] Furthermore several pore forming toxinsresult in an increased intracellular Ca2+ that triggers NLRP3activation [41] Nevertheless changes in intracellular ionconcentration would also stimulate other inflammasomecomplexes which argues against ion flux as the exclusivecause for NLRP3 inflammasome activation
23 Lysosomal Rupture and Cathepsin B Release Destabi-lization of the acidic lysosomal compartment and release oflysosomal protease cathepsin B into the cytoplasm duringphagocytosis of large particles or crystals such as silicaasbestos uric acid or beta-amyloids have also been impli-cated in the activation of the NLRP3 inflammasome [42]Furthermore phagocytosis could also induce K+ effluxAdditionally lysosomes contain high concentration of Ca2+and lysosomal rupture results in the release of Ca2+ intothe cytosol triggering further Ca2+ release from the ERHowever the molecular details and connections of theseevents are not yet clarified In conclusion although NLRP3inflammasome is themost intensively studied inflammasomecomplex it is still unclear which mechanisms are responsiblefor its activation
24 Mitochondrial Dysfunction In response to infection orendogenous stimuli the perturbation of intracellular ROSK+ or lysosomal stability leads to mitochondrial dysfunctionand to the release of mitochondrial DAMPs such as mtDNAcardiolipin or dynamin-related protein 1 (Drp1) [43] Itwas shown that due to increased mtROS level releasedmtDNA is oxidized and activatesNLRP3 inflammasome [26]Cardiolipin is a non-bilayer-forming phospholipid foundin bacteria and in the inner mitochondrial membrane ofeukaryotes and its translocation from the inner membraneto the outer membrane was shown to activate NLRP3 inflam-masomedownstreamofmtROS [44] It was also reported thatGTPaseDrp1 that is needed for the fragmentation and aggre-gation of mitochondria also induces NLRP3 inflammasomeactivation and IL-1120573 secretion in response to VSV infectionbut not to ATP or nigericin [45] Moreover mitofusin anouter mitochondrial GTPase that regulates mitochondrial
fusion was also described as an NLRP3 activator duringviral infection [46] Recently it was described that themitochondrial antiviral signaling protein (MAVS) located inthemitochondrialmembranemediating interferon responsesalso induces NLRP3 inflammasome activation [47] Thesereports demonstrate that the mitochondrion is a complexregulator of cytosolic homeostasis and a central platform forNLRP3 inflammasome activation
25 Autophagy Autophagy is an evolutionarily conservedmechanism to maintain cellular homeostasis by selectivelyeliminating damaged or aging organelles microbes andubiquitinated proteins through the formation of autophago-somes and using lysosomal degradation Lines of evi-dence show that autophagy suppresses organelle stress-induced activation of NLRP3 inflammasome Furthermoreit was reported that inducers of autophagy also inducethe autophagosomal engulfment of IL-1120573 and its lysosomaldegradation [48] It was also shown that damaged mitochon-dria accumulate in autophagy-deficient macrophages that inturn lead to increased intracellular ROS and to the release ofmtDNA [49]
26 Spatial Location of NLRP3 Originally it was shownthat activated NLRP3 inflammasome localizes to the mito-chondria However recently it was described that duringinflammasome activation ER-associated NLRP3 colocalizeswith the mitochondria-associated ASC to the perinuclearspace via a microtubule-mediated organelle transport It wasshown that upon cell activation the decreased intracellularNAD+ level leads to the inhibition of sirtuin 2 (SIRT2)deacetylase resulting in the accumulation of acetylated alfa-tubulin triggering a dynein-dependent transport of mito-chondria to the perinuclear region into the close proximityto the ER [50]
3 NLRP3 Inflammasome and Related Diseases
Understanding the steps and mechanism of NLRP3 inflam-masome activation would be of crucial importance forthe treatment of several diseases in which the inflamma-some complex has been implicated By producing IL-1120573inflammatory cytokine and inducing pyroptosis the primaryfunction of NLRP3 inflammasome is to protect the hostfrom invading microorganisms [78] However nonmicrobialcompounds of either endogenous (self-derived) or exogenous(environmental) origin are also effective inducers of NLRP3inflammasome activation and lead to sterile inflammationallergic responses or other forms of inflammation [79] Forexample studies have shown that NLRP3 may be implicatedin Alzheimerrsquos disease suggesting that misfolded A120573 pro-teins form aggregates that lead to the activation of NLRPinflammasome [80 81] In gout MSU crystals from purinedegradation form deposits in different tissues and specif-ically activate NLRP3 inflammasome [14] Environmentalparticulates such as inhaled asbestos and silica also activateNLRP3 inflammasome and the high concentration of IL-1120573 is involved in the development of asbestosis and silico-sis two progressive pulmonary diseases leading to fibrosis
4 Mediators of Inflammation
[16 82] NLRP3 inflammasome has also been related toallergic responses to a variety of allergens such as aluminumdust mite or ragweed pollen however the molecular detailsof these responses are still not clear [83ndash85]
Other studies associated NLRP3 inflammasome functionwithmetabolic syndrome and type 2 diabetes as NLRP3 defi-cient mice were protected from high fat diet- (HFT-) inducedinflammation glucose intolerance insulin resistance andobesity [86 87]
The dysregulated production of IL-1120573 by the NLRP3inflammasome is the main reason for the development ofCryopyrin-Associated Periodic Syndromes (CAPS) which iscaused by a mutation in NLRP3 gene CAPS is an autoin-flammatory disorder rather than an autoimmune one assymptoms aremediated by the innate immune systemmainlyby monocytes and macrophages that produce huge amountof IL-1120573 Behcetrsquos disease (BD) is another chronic autoin-flammatory disorder of unknown etiology and increasedIL-1120573 production has been noted as a central player in thepathogenesis of this disease Studies demonstrated increasedROS production and consequently increased NLRP3 func-tion in these patients suggesting an important role forNLRP3inflammasome in mediating cytokine production [88] Inaddition to autoinflammatory diseases NLRP3 inflamma-some function has also been implicated in the developmentof autoimmune diseases like rheumatoid arthritis (RA) [89]RA is a common inflammatory disease affecting small jointsand our knowledge about its pathogenesis is still incompleteNevertheless elevated levels of IL-1120573 and high expression ofNLRP3 were detected from the serum and synovial tissue aswell as in macrophages of RA patients [90]
At present the role of NLRP3 inflammasome and IL-1120573 in cancer is highly controversial The microenvironmentof tumors is characterized by an inflammatory milieu thathelps tumor survival with growth hormones endothelialactivation and angiogenesis that leads to metastasis accom-panied by immune suppression IL-1120573 participates in each ofthese mechanisms by stimulating the expression of TNF120572MMPs VEGF ICAM-1 VCAM and so forth Cancer cellslike melanoma or myeloma as well as tumor-associatedmacrophages and dendritic cells were shown to contribute tothe IL-1120573 production that helps survival and growth of tumorcells furthermore excessive production of IL-1120573 can recruitimmunosuppressive cells like myeloid-derived suppressorscells (MDSCs) [91] On the other hand it was also shown thatNLRP3-induced IL-1120573 production boosts T cell function inpatients receiving chemotherapy [92]
The classical medical approach to treating the above-mentioned diseases involves the use of synthetic drugs devel-oped against individual elements of the signaling pathwaythe IL-1120573 cytokine or the IL-1120573 receptor as reviewed inOzaki et al 2015 [93] However today in the health-cautiouslife era the use of botanical and natural compounds hasgained popularity While a few decades ago the use of naturalcompounds was based exclusively on empirical experiencestoday with the highly developed molecular biological highthroughput methods many molecular elements of theiraction have already been identified However fundamentalquestions remain to be answered including bioavailability
effective doses body concentrations cross-reactivity half-life and degradation and synergistic effect of compoundsas well as carefully designed clinical trials The aim of thepresent review is to provide an overview of these plant-derived natural compounds that would support the use ofmedicinal plants (Figure 2) As a variety of compounds caninfluence inflammasome activation and function we havefocused on natural compounds that have been in long termuse in traditional medicine therefore their safety and overalleffect are mostly established However these compoundstypically influence a multitude of pathways and the exactmolecular mechanisms of their beneficial actions are notcompletely clarified (Table 1)
41 Aloe vera Aloe vera is a medical plant used traditionallyin diverse therapeutic applications The gel of Aloe verahas been reported to stimulate wound-healing and skinhydration induce hematopoiesis and possess antidiabeticanticarcinogenic antimicrobial and antioxidant as well asanti-inflammatory activities Over 75 active components havealready been identified in Aloe vera leaf gels [94] andsome of them have been implicated as immunomodulatorycompounds based on animal studies In amouse sepsismodeland in a human colorectal mucosa model treatment withAloe vera significantly inhibited the elevation of TNF120572 IL-6 and IL-1120573 levels [95 96] Studying human THP-1 cellsand human monocyte-derived macrophages it was foundthat Aloe vera treatment significantly reduced LPS-inducedIL-1120573 production [51] Aloe vera inhibited the expressionof pro-IL-1120573 NLRP3 and caspase-1 as well as that of theP2X7 receptor in the LPS-induced primary macrophagesFurthermore LPS-induced activation of signaling pathwayssuch as NF-120581B p38 JNK and ERK were inhibited by Aloevera in these cells [51]
Aloe emodin is an anthraquinone present naturally inAloe leaves It has been shown to promote natural killer cellactivity andmacrophage phagocytosis in tumor [97] Emodinitself appears to have some protective effect in the inflamma-tory response Recently it was shown that emodin attenuatednigericin- ATP- and silica-induced IL-1120573 secretion fromLPS-activated murine bone marrow-derived macrophages(BMDMs) It was also shown that mice treated intraperi-toneally with emodin showed higher survival rates than con-trol mice injected with LPS alone indicating that emodin canameliorate the severity of NLRP3 inflammasome-mediateddisease symptoms in vivo [52] However further moleculardetails of the inhibitory effect are yet to be discovered
42 Curcumin Curcumin is a lipid soluble polyphenol ayellow pigment isolated from the rhizomes of Curcuma longa(turmeric) but also found in other plants like ginger It iswidely used in food coloring and flavoring and it is also addedto cosmetics It has gained attention in recent years for itsmultiple pharmacological properties being antioxidant anti-inflammatory and antimicrobial as well as for its therapeutic
Mediators of Inflammation 5
O
O
OHOH
OH
Emodin
O O
OHHO
Curcumin
O
O
HO
OH
OH
OH
OHQuercetin
O
SN
CS
Sulforaphane
O
OH
OH
HHO
Genipin
O
O
O
OH
OH
OH
HO
OH
OH
OH
EGCG
O
O
O OH
OH
OH
OH
HO
HO
HOMangiferin
OH
OH
OH
OH
OGlc
OGlcGinsenoside
(basic)
OH
OH
OH
HO
OH
HO
Resveratrol
trans- cis-
H3C
H3CO
OCH3
OCH3
CH3
Figure 2 Chemical structure of natural compounds influencing NLRP3 inflammasome activation
potential in cancer autoimmune metabolic pulmonarycardiovascular and neurological diseases (reviewed in [98])
Brain ischemia is known to induce ER stress and inflam-matory responses leading to neuronal damage [99 100] Ina recent study glucose deprivation or hypoxia was reportedto strongly induce the production of glutamate and IL-1120573 inmouse hippocampus [53] It was shown that pretreatmentof the mouse hippocampus with curcumin reduced IL-1120573 production and this effect was attenuated by 51015840-AMP-activated protein kinase (AMPK) inhibitor suggesting thepossible involvement of AMPK The authors also foundthat curcumin attenuated glutamate-induced phosphoryla-tion of PERK and IRE1120572 the transmembrane sensors ofER stress that mediate inflammatory signals Moreoverusing a neuroblastoma cell line they showed that curcumininhibited glutamate-induced ROS generation as well asreduced glutamate-induced TXNIP expression As a possiblemolecular mechanism they found that in mice hippocam-pus glutamate stimulation increased NLRP3 expression andthe cleaved form of caspase-1 enzyme while curcuminattenuated NLRP3 and cleaved caspase-1 expression Theproduction of IL-6 a downstream target of IL-1120573 was alsoinhibited by curcumin treatment In addition curcumineffectively attenuated mitochondrial function and preventedcaspase-3 activation in hippocampus exposed to glutamate
stimulation effectively preventing glutamate-induced cellapoptosis Furthermore in rats curcumin administrationattenuated ischemic brain injury resulting from middlecerebral artery occlusion (MCAO) Based on these findingscurcumin activates AMPK that inhibits glutamate-inducedER stress and ROS production thus inhibiting TXNIP-induced NLRP3 inflammasome activation and ultimatelyreducing IL-1120573 production in mouse hippocampus limitingbrain injury
Macrophages are popular models for the study ofNLRP3 inflammasome activation In another study per-formed on mouse macrophage cell line J774A1 and peri-toneal macrophages curcumin was shown to strongly inhibitIL-1120573 secretion triggered by LPS plus nigericin aluminumATP or MSU [54] Preincubation with curcumin preventednigericin-induced intracellular potassium level decreaseattenuated lysosome damage and cathepsin B leakage andblocked high mobility group box 1 (HMGB-1) release need-less to say all of these are components that may induceNLRP3 inflammasome activation In BMDMs curcumininhibited nigericin- or aluminum crystal-induced ROS pro-duction The authors did not find obvious inhibitory effectof curcumin on JNK and p38 phosphorylation enhancedby nigericin treatment in the LPS-primed macrophageshowever they found that ERK12 phosphorylation was
6 Mediators of Inflammation
Table 1 Natural compounds effecting NLRP3 inflammasome-mediated IL-1 production
Compound Effect Mechanism Target cell Reference
Aloe vera extract Reduced IL-1120573
Reduced expression of NLRP3procaspase-1 and P2X7RInhibition of ERK p38 NF120581Bsignaling
THP-1 and human MF [51]
Aloe emodin Reduced IL-1120573 Reduced expression of NLRP3procaspase-1 and ASC expression BMDM [52]
Aloe emodin Enhanced survival NLRP3-KO mice model of septicshock [52]
Curcumin Reduced IL-1120573 andcaspase-1 inhibition Reduced ER stress through AMPK Mouse hippocampus [53]
Curcumin Reduced ROS and TXNIP expression Neuroblastoma cells [53]
Reduced expression of NLRP3 ASCand caspase-1Reduced ROS and reducedmitochondrial dysfunctionActivation of AMPK and autophagy
Murine hepatocytes [77]
dramatically downregulated In a mouse model of LPS-induced septic shock administration of curcumin signif-icantly decreased ROS level and cathepsin B leakage inperitoneal macrophages additionally peritoneal HMGB-1and IL-1120573 concentrations were downregulated resulting ina reduced LPS-induced splenomegaly These data suggestthat the observed reduction of secreted mature IL-1120573 bycurcumin is primarily attributed to the inhibition of NLRP3inflammasome activation
43 EGCG Epigallocatechin-3-gallate (EGCG) is the majorbioactive polyphenol in green tea that has a well-documentedantioxidant activity as it functions as a free-radical scavengerEGCG was reported to inhibit NF120581B activation and thesubsequent expression of several inflammatory moleculessuch as inducible nitric oxide synthase (iNOS) matrixmetalloproteinases (MMPs) IL-6 and TNF120572 Besides theanti-inflammatory role EGCG was also thought to possessantitumor effect [101]
In unilateral ureteral obstruction mice model renalinflammation has been linked to the activity of NLRP3inflammasome and the overproduction of IL-1120573 Further-more the role of NLRP3 inflammasome was proven in a vari-ety of human nondiabetic and chronic kidney diseases [102]It was reported that EGCG can prevent the development of
lupus nephritis when administered to NZBW F1 mice theclassical model of systemic lupus erythematosus [55] Thesestudies showed that EGCG treatment activated Nrf2 antiox-idant pathway induced the expression of Nrf2 downstreamenzymes like NAD(P)H dehydrogenase (quinone) 1 (NQO1)and heme oxygenase 1 (HO-1) and reduced renal oxidativestress Furthermore EGCG inhibited renal NLRP3 inflam-masome activity and the expressions of NLRP3 caspase-1and IL-1120573 were also reduced possibly due to the EGCG-induced attenuation of NF120581B pathway activity
Very recently the beneficial effect of EGCG was reportedin a contrast-inducednephropathy (CIN) ratmodel [56] CINis a common iatrogenic cause of acute kidney injury (AKI)after exposure to iodinated contrast medium characterizedby oxidative stress and inflammation [103] Similar to theprevious study they found that EGCG treatment reducedoxidative stress and increased Nrf2 and HO-1 expressionThey also found that EGCG reduced the elevated IL-1120573secretion and NLRP3 protein expression The molecularmechanisms of the observed results however were notstudied
44 Genipin Genipin is a water-soluble bifunctional cross-linking reagent that was initially isolated from the Chinesemedicinal plant Gardenia jasminoides (common name jas-mine) and it has been used for centuries as a herbal medicine
8 Mediators of Inflammation
to protect the liver and gallbladder It possesses antihyper-tensive antibleeding and antiswelling properties in additionto exhibiting anti-inflammatory characteristics Chemicallyit is an aglycone derived from an iridoid glycoside calledgeniposide that is enzymatically hydrolyzed to genipin byintestinal bacteria when administered per os [104] Genipinwas reported to inhibit mitochondrial uncoupling protein2 (UCP2) as well as superoxide-activated UCP2-mediatedproton leak occurring in a variety of diseases [105]
Recently it was shown that overexpression of UCP2caused a significant increase in NLRP3 expression in THP-1 cells and this was significantly inhibited by the adminis-tration of genipin while the levels of the adaptor proteinASC did not change [57] Interestingly genipin treatmentattenuated IL-1120573 levels in LPS-primed cells treated with ATPhowever this effect was not observed in cells treated withnigericin In addition it was also shown that inhibition ofATP-mediated inflammasome activation by genipin does notalter the production of other proinflammatory cytokines suchas IL-6 and TNF120572
In another recent study in LPS-primed murine BMDMsgenipin dramatically inhibited IL-1120573 secretion of LPS-primedcells following ATP nigericin MSU crystals or Listeriamonocytogenes treatment [58] Furthermore genipin alsoinhibited the Salmonella typhimurium-induced secretion ofIL-1120573 which is mediated via the activation of NLRC4inflammasome Similar to the previous study LPS-dependentTNF120572 secretion was not impaired by genipin Importantlygenipin treatment did not inhibit the expression of pro-IL-1120573 pro-caspase-1 or ASC proteins however it inhibitedNLRP3-dependent ASC oligomerization in addition to IL-1120573secretion and caspase-1 activation In contrast to its inhibitoryeffect on NLRP3-mediated ASC oligomerization genipindid not affect NLRC4-mediated formation of ASC speckleswhileNLRC4-mediated caspase-1 activationwas significantlydiminished These data indicate that the inhibitory effect ofgenipin on NLRC4 inflammasome activation is independentof ASC
45 Ginseng White ginseng is the naturally dried formof ginseng (Panax ginseng) while red ginseng is made bysteaming and drying fresh ginseng root Red ginseng hasbeen used for centuries as an immune-modulator and hasalso been used as an adjuvant in the treatment of infectiousand metabolic diseases Korean red ginseng contains variousactive components including saponins such as ginsenosidesand nonsaponins such as polysaccharides peptides fattyacids and mineral oils Ginsenosides are the major activecomponents of ginseng They reduce the production ofinflammatory cytokines by inhibiting NF120581B signaling [106]They also have amphiphilic nature and are able to intercalateinto the plasma membrane and influence membrane fluidityand function
It was shown that red ginseng extract (RGE) inhibitedATP- nigericin- and aluminum-induced IL-1120573 secretionin LPS-primed BMDMs and THP-1 cells and amelioratedlethality in LPS-induced septic shock model of mice [59]Furthermore RGE attenuated IL-1120573 secretion in dsDNA-transfected macrophages Similar results were obtained for
ginsenosides Furthermore it was also shown that RGE actedas an inhibitor of both NLRP3 and AIM2 inflammasomeactivations It was also demonstrated that RGE attenuated thesecretion of the active form of caspase-1 (p20)
It was previously reported that endogenousNOproducedby iNOS inhibits NLRP3 inflammasome activation via theS-nitrosylation of NLRP3 protein [107 108] A recent studyreported that ginsenosides negatively regulates LPS-inducedseptic shock in mice by a mechanism involving inhibitionof iNOS expression and the subsequent NO production[60] It was shown that ginsenosides reduced NO leveliNOS expression and ROS level in peritoneal macrophagesand BMDMs after LPS stimulation They also found thatginsenoside treatment attenuated S-nitrosylation of NLRP3protein which resulted in increased IL-beta secretion in LPS-activated macrophages
46 Mangiferin Mangiferin is a water-soluble naturalpolyphenol with a C-glycosylxanthone structure The pri-mary source of mangiferin is the mango tree (Mangiferaindica) however it is also present in some medicinal herbsin Iris unguicularis and in the honeybush a popular herbaltea from South Africa It possesses a wide spectrum ofbeneficial effects on health being used as an analgesicantidiabetic antisclerotic antimicrobial and antiviral as wellas being praised for its anti-inflammatory effects It has beenshown to regulate AMPK activity and in a recent work itwas reported that in human endothelial cells exposed tohigh glucose mangiferin reduced IL-1120573 secretion [61] Fur-thermore mangiferin attenuated IRE1 phosphorylation andreducedROS production and it decreased TXNIP expressionand inhibited ER stress Moreover a decrease in NLRP3expression and IL-1120573 production was also demonstrated
Very recently the protective role of mangiferin wasdescribed in LPS plus D-galactosamine- (D-GalN-) inducedacute liver injury [62] The authors showed that mangiferinreduced IL-1120573 secretion and ROS production and it alsoinhibited iNOS expression but induced Nrf2 and HO-1expression Furthermore it attenuated NLRP3 ASC andcaspase-1 (p10) expression and the subsequent IL-1120573 produc-tion
47 Propolis Propolis is a resinous material produced bybees (Apis mellifera L) through the mixing of secretions andenzymes from their hypopharyngeal glands with the budsof plants and wax A few hundred compounds have beendetected in raw propolis including polyphenols terpenoidssteroids sugar and amino acids Propolis composition islargely influenced by botanical origins and geographicallocation as well as by collection season One of the mostknown biological activities of propolis is related to its anti-inflammatory effect Artepillin C is a simple phenol com-posed of a single ring with two prenyl groups (35-diprenyl-4-hydroxycinnamic acid) and is the major biologically activephenolic ingredient identified in green propolis derived fromSoutheast Brazil [109]
The role of artepillin C was studied on the oxidativemetabolism of PMA-stimulated RAW2647 macrophages[63] It was shown that artepillin C significantly inhibited
Mediators of Inflammation 9
ROS release upon the NLRP3 activator nigericin treatment Itwas also suggested that artepillin C significantly contributedto the modulation of chemokine-mediated inflammation asit significantly downregulated the release of IL-1120573 IL-12p40and TNF120572 by LPS + IFN120574-treated RAW2647 cells whereasthe synthesis of IL-1120572 and IL-6 was not affected Besidesnigericin-mediated IL-1120573 production propolis also inhibitedLegionella pneumophila-induced IL-1120573 cytokine secretionin LPS-primed BMDMs This indicates that both NLRP3and NLRC4 inflammasome functions may be regulated bypropolis however further studies are required to clarify thedetailed molecular mechanism of the observed results
48 Quercetin Quercetin a kind of flavonoid found in avariety of vegetables beverages fruits and herbs exhibitsanti-inflammatory and antioxidant properties Quercetinwasreported to reduce inflammation in visceral adipose tissueprimary human adipocytes and the kidney of fructose-fedrats It was also shown to prevent diabetic kidney injury inratsHowever themechanisms of the action of quercetinwerenot clarified
It has been described that quercetin attenuated fructose-induced hyperuricemia and renal dysfunction In a studyusing streptozotocin- (STZ-) induced diabetic nephropa-thy rat model leading to hyperuricemia and dyslipidemiaquercetin was found to block NLRP3 inflammasome acti-vation [64] It was shown that the STZ-induced expres-sion of inflammasome components was restrained and IL-1120573 secretion was reduced by quercetin treatment Similarresults were obtained studying inflammatory responses infructose-induced hyperuricemia in rat [65] They showedthat fructose significantly elevated the expression of renalNLRP3 ASC and caspase-1 expression while quercetintreatment ameliorated the expression of these proteins Basedon their findings it was suggested that fructose-mediatedrenal NLRP3 inflammasome activation and proinflamma-tory cytokine overproduction may be associated with theimpaired cross talk between renal JAK2-STAT3 and PPAR-120572signaling pathway that in turn regulate renal inflammation
Furthermore it was shown that quercetin markedlyinhibited the overexpression of hepatic TXNIP in additionto reducing the production of ROS and the activation ofNLRP3 inflammasome consequently resulting in decreasedIL-1120573 secretion [66 110]They also showed that the decreasedcaspase-1 activity downregulated the caspase-1-dependentactivation of SREBPs that are involved in fatty acid andcholesterol synthesis They suggested that regulation of theTXNIP-NLRP3-SREBPs pathway by quercetin may partiallymediate the alleviation of hepatic steatosis in these diabeticrats
It was also shown that quercetin treatment regulatedAMPK pathway activation glutamine-glutamate cycle dys-function and TXNIP overexpression moreover it sup-pressed NF120581B pathway eventually leading to impairedNLRP3 inflammasome activation and IL-1120573 production inthe hypothalamus of high fructose- (HF-) fed rats [67]
Using human umbilical vein endothelial cells anothergroup reported that quercetin suppressed palmitate- (PA-) induced IL-1120573 and IL-6 induction [68] Downregulation
of NLRP3 induction was probably partially mediated viathe inhibition of ROS production and TXNIP expressionquercetin also inhibited IKK120573 activation by attenuatingits phosphorylation Furthermore quercetin treatment pro-tected cells against PA insult and significantly reduced thenumber of apoptotic cells Moreover quercetin amelioratedER stress-induced endothelial dysfunction through the acti-vation of AMPK
NLRP3 inflammasome is also recognized to have animportant role in the spinal cord tissue after traumatic spinalcord injury (SCI) and targeting the NLRP3 inflammasomecan inhibit neuroinflammation thereby improving func-tional recovery in SCI rats [111]
Very recently in a ratmodel of SCI quercetin administra-tion was shown to significantly improve functional recovery[69] Histopathological changes of the spinal cord such ascongestion edema neutrophil infiltration and structuraldisruption were inhibited by quercetin administration Toformulate a molecular mechanism the authors showed thatquercetin administration significantly reduced inflammatorycytokine IL-1120573 IL-18 and TNF120572 levels it also reduced theNLRP3 ASC and active caspase-1 protein expression andROS production However further studies are needed tobetter characterize the mechanisms of action underlying thebeneficial effects of quercetin in inflammation and immunity
49 Resveratrol Resveratrol is a polyphenol present inthe skin of grapes and mulberry commonly used in redwine production The beneficial effects of resveratrol arethought to be mediated in part by its antioxidant andanti-inflammatory properties exhibiting beneficial effectsin several diseases [112] Resveratrol exists as two isomerscis- and trans-resveratrol The cis isomer is thought to beproduced naturally during grape fermentation as a resultof isomerization of the trans isomer by yeast isomerasesFurthermore cis-resveratrol can be obtained by exposure ofthe trans isomer to sunlight Several studies have shown thattrans-resveratrol exhibits a wide range of biological activitiesincluding anti-inflammatory antioxidant anticarcinogenicantiaging antiplatelet aggregation immune-modulatory andchemoprevention effects However only few studies havebeen performed to examine the biological effects of the cisisomer Studies on cis-resveratrol have demonstrated thatit also possesses anticancer antimicrobial and antiplateletaggregation activities
One of the biological roles of resveratrol is to initiate theactivation of sirtuin 1 (Sirt1) is a deacetylase that modifies andinactivates inflammatory genes At high doses resveratrolhas been shown to activate AMPK which is involved inthe negative regulation of the NLRP3-inflammasome [113]It was also shown that ionizing radiation-induced IL-1120573secretion by human mesenchymal stem cells (MSCs) aneffect that was effectively abrogated by pretreatment withresveratrol [70] Radiation-induced increase in IL-1120573 occursvia the NLRP3 inflammasome activation however resver-atrol treatment attenuated the expression of NLRP3 It wasalso demonstrated that resveratrol treatment upregulated theexpression of Sirt1 In conclusion it is suggested that Sirt1
10 Mediators of Inflammation
inhibits NF120581B transcriptional activity through deacetylationthat in turn limits the transcription of NLRP3
In another study it was shown that cis-resveratrol pre-treatment significantly inhibited IL-1120573 secretion in THP-1 cellculture supernatants interestingly cis-resveratrol inducedIL-18 secretion under these conditions [71] Accordingly cis-resveratrol significantly reduced IL-1120573 mRNA expressionin contrast cis-resveratrol used at the same concentra-tion increased IL-18 mRNA expression Furthermore cis-resveratrol increased the mRNA and protein levels of NLRP1and NLRP3 indicating that the inhibitory effect of cis-resveratrol on IL-1120573 secretion is not due to the down-regulation of NLRP1 NLRP3 or ASC expression Similarresults were obtained on LPS-primed J774A1 macrophageswhere resveratrol inhibited the ATP-induced IL-1120573 secretionhowever in this study the authors did not find changes in theexpression of NLRP3 [72] showing that the resveratrol didnot inhibit the priming signal of NLRP3
Huang et al suggested that the inhibitory effect of cis-resveratrol on IL-1120573 secretion may be due to the reducedexpression of purinergic receptor P2X7R and the ER stressmarker GRP78 which leads to suppression of ROS pro-duction and reduced caspase-1 and caspase-4 activation Itwas found that cis-resveratrol also inhibited cyclooxygenase-(COX-) 2 expression which may be responsible for theobserved decrease of PGE2 production Furthermore inhi-bition of pro-IL-1120573 and COX-2 expression may occur bydownregulating the activation of the p38 MAPK path-way [71] Importantly in contrast to these observationsincreased phosphorylation of p38 was detected in ATP-activated J774A1 macrophages by Chang et al while itdid not significantly increase the phosphorylation levelsof ERK12 and it reduced the phosphorylation levels ofJNK12 The levels of mtDNA release into the cytosol weresignificantly reduced by resveratrol indicating that therewas less mitochondrial injury in resveratrol-treated cells[72] Furthermore the authors also showed that resveratrolincreased cellular cAMP level in J774A1 macrophages whichacts as a negative regulator of inflammatory responses andinhibits NLRP3 inflammasome activation
The effect of resveratrol on NLRP3 inflammasome wasfurther proved by a study showing that four weeks ofresveratrol administration inhibited the expression of NLRP3inflammasome components IL-1 IL-6 and TNF120572 and inlivers of HF-fed mice [73] They also showed that theregulatory effects of resveratrol on NLRP3 inflammasomemay come about through the combined effects of Sirt1 andSirt6
In a recent study [50] it was found that resveratroltreatment successfully suppressed the maturation of bothIL-1120573 and caspase-1 in response to Pam3CSK4 a TLR12agonist plus various inducers (like nigericin ATP MSUand silica) of the NLRP3-inflammasome In mouse BMDMshowever it did not affect the production of IL-1120573 medi-ated by the NLRC4-inflammasome (flagellin) or the AIM2-inflammasome (dsDNA) On a mouse model of acute goutthey indicated that resveratrol reduced the amount of matureIL-1120573 and the subsequent recruitment of neutrophils intothe peritoneal cavities of mice after challenge with MSU
crystals These findings indicate that resveratrol suppressesthe activation of the NLRP3-inflammasome both in vitroand in vivo As a possible mechanism they showed thatresveratrol at a substantially higher dosage successfullysuppressed mitochondrial ROS production Furthermoreresveratrol treatment prevented the accumulation of acety-lated 120572-tubulin thusinhibiting the proximate localization ofASC and NLRP3 in macrophages
In a very recent publication [74] the authors showed thatresveratrol preventedATP-inducedNLRP3 activation and IL-1120573 production in the BV2 cell line and in septic mice as wellThey also found that resveratrol treatment reduced NLRP3and IL-1120573 expression in the hippocampus of the mice andthey suggested that the protecting effect of resveratrol wasmediated via the increased expression of Sirt1 in BV2 cells
Another recent publication found that glucose-basedperitoneal dialysis increased mitochondrial ROS productionand subsequent IL-1120573 secretion through NLRP3 inflamma-some in human peritoneal mesothelial cells (HPMC) Asa mechanism for its action they showed that resveratrolinduced mitophagyautophagy of the cells via AMPK activa-tion and protected cells fromROS-inducedNLRP3-mediatedinflammatory injury [75]
410 Sulforaphane Sulforaphane (SFN) is a natural com-pound present in cruciferous vegetables such as broccolicabbage Brussel sprouts mustard and radish ChemicallySFN is an isothiocyanate that is known to react withsulfhydryl groups and tomodify proteins at cysteine residuesSulforaphane is produced from the precursor glucoraphaninby the enzymatic activity of myrosinase when the cell wallsof the plant are damaged for example during chewingSFN has been known as a cytoprotective agent for cancerprevention or treatment and it also has an important rolein cardiovascular neurologic and other diseases (reviewedin [114]) SFN is a known inducer of the Nrf2 antioxidantpathway as it activates the Nrf2 transcription factor byreacting with cysteine residues of its repressor Keap1 [115]In addition it also inhibits NF120581B signaling [116]
It was shown that SFN inhibited IL-1120573 processing byNLRP1- NLRP3- NLRC4- and AIM2- inflammasome com-plexes in mouse BMDMs [28] It was also demonstratedthat SFN inhibits the inflammasome in an Nrf2-independentmanner as SFN-mediated inhibition of NLRP3- andNLRC4-dependent IL-1120573 processing and secretion was not reversedin Nrf2-knockout BMDMs When SFN was added directlyto the cell lysates it did not inhibit IL-1120573 processingdemonstrating that SFN does not directly inhibit the proteaseactivity of caspase-1 The authors found that SFN-mediatedinhibition of the inflammasomes is not affected by ROSmodulation and neither proteasome-dependent proteolysisnor de novo protein synthesis is required for SFN-mediatedinhibition of the inflammasomes In a peritonitis model ofacute gout SFN treatment significantly reducedMSU crystal-induced IL-1120573 production demonstrating that SFN inhibitsthe NLRP3 inflammasome function in vivo Nonethelessthe authors concluded that SFN inhibits multiple inflam-masomes in vitro and in vivo by a mechanism independent
Mediators of Inflammation 11
ERKp38
NLRP3
ASCNLRP3
Caspase-1ROS
ER stress
P2X7R ATP
Cathepsin B
TLR
ROS
mtDNA
Sirt2
AcAc
AcAc
AMPK
A
A AC
C
C
Nrf2E
E
UCP2Ge
Ge
Ge
Gi
TXNIPC
NOGi
P
Sirt1R
R
R
R
M
M
M
Q
QQ
SS
S
R
Cardio-lipin
Acetylated 120572-tubulin
Ca2+ influx
IL-1120573
Pro-IL-1120573
K+efflux
120572-Tubulin
Pro-IL-1120573
NF120581B
Figure 3 Molecular targets of natural compounds affecting NLRP3 inflammasome-mediated IL-1 production
of inflammasome priming and Nrf2 signaling however theexact molecular mechanism was not explored
As SFN is able to penetrate the blood-brain barrier[117] it gained a considerable attention as a candidatefor Alzheimerrsquos disease (AD) therapy SFN was shown toprotect the brain from A120573-induced oxidative cell death viaactivation of Nrf2 signaling cascade [118] As A120573 fibrilshave been shown to activate NLRP3 inflammasome thequestion arose whether SFN may regulate this mechanismIn a very recent study it was shown that SFN significantlydownregulated IL-1120573 production and NLRP3 expression inA1205731ndash42 peptide-stimulated human THP-1 cells macrophages[76] It was found that A1205731ndash42 peptide-induced STAT-1phosphorylation was significantly attenuated by SFN Theauthors showed that SFN inducedNrf2 nuclear translocationwhich was subsequently accompanied by an increase in HO-1 protein levels Furthermore A1205731ndash42 peptide-induced IL-1120573 production was diminished by siRNA-mediated knock-down of Nrf2 or HO-1 They also found that the increasedproinflammatory miRNA-146a level following A1205731ndash42 treat-ment was significantly attenuated by SFN whereas miRNA-125b and miRNA-155 levels were not changed These arespecific proinflammatory miRNAs that were reported to beincreased in both the extracellular fluid and cerebrospinalfluid of AD patients In conclusion SFN can suppress A1205731ndash42-induced caspase-1-dependent inflammasome activationpossibly through inhibiting STAT-1 phosphorylation andactivation of the Nrf2HO-1 signaling pathway
Also very recently another research group reported thatoral administrations of SFN suppressed the saturated fattyacid-induced NLRP3 inflammasome activation in the liverof mice [77] They found that SFN decreased the expression
of ASC caspase-1 and IL-1120573 levels additionally it inhibitedthe activity of caspase-1 enzyme in primary hepatocytes Itwas also shown that SFN reduced the palmitate-inducedROS production by the mitochondria implying that SFNprevented mitochondrial dysfunction and this protectingmechanism was in part mediated by the activation of AMPKThey concluded that activation of AMPK and autophagy bySFN could protect from mitochondrial dysfunction inducedby saturated fatty acids resulting in a downregulation of fat-induced activation of the NLRP3 inflammasome
5 NLRP3 Inflammasome and theXenohormesis Hypothesis
As it was described in detail above polyphenols like resvera-trol curcumin EGCG and quercetin are potent inhibitors ofNLRP3 inflammasome-mediated IL-1120573 production typicallyacting at more than one element of the involved pathways(Figure 3)However it should be noted that these polyphenolshave an evenmuch broader biological effect as they influencea variety of pathways [119] though not all are directlyconnected to the function of the NLRP3 inflammasomeImportantly more than 8000 natural polyphenols have beendescribed [120] providing a large library of compounds aspotential inflammasome inhibitors Many of these polyphe-nols (such as resveratrol and curcumin) are overproducedby stressed plants triggering pathways mimicking the effectof caloric restriction It has been proposed that organismsfrom yeast to humans consuming stressed plants couldinterpret the stress signal carried by such polyphenols as apotential risk of future limitation of food availability and in
12 Mediators of Inflammation
turn adapting for the pursuit of longevity a theory termedas Xenohormesis [121ndash123] Interestingly the structurallyunrelated resveratrol and curcumin can achieve this caloricrestriction mimicking effect by activating AMPK and Sirt1[124] However polyphenols are also known to have anantioxidant effect activate glutathione S-transferases andinhibit COX enzymes among many other effects [125 126]Interestingly one of the most frequently used COX inhibitoris aspirin a derivative of another stress-induced phytochem-ical salicylic acid
A major concern of polyphenol use in therapy is thebioavailability of these compounds Nevertheless typicaldietary polyphenol intake is about 14mgkgday which iswithin the range of providing biologically active doses [127]
6 Concluding Remarks
Most of the time inflammasome-mediated IL-1120573 productionor caspase-mediated pyroptosis is beneficial for the host as itprotects from infection or prevents further damageHoweverprolonged cytokine production as in the case of sterileinflammation caused by endogenous danger signals maylead to the development of autoinflammatory or metabolicdiseases Chronic inflammation compromises the hostrsquos lifequality and requires sustained pharmacological and surgicaltreatments The paradigm of drug discovery in Westernmedicine is to develop highly selective compounds againstindividual druggable targets Currently the main treatmentmethods for these patients are targeting IL-1120573 Howeverprolonged usage of drugs may induce different side effectsfurthermore some form of medications are very expensivewhich limits their widespread use
Besides the high expenses another drawback of tradi-tional drug design is that many of the promising compoundsfail in the early or later stages of drug development Tradi-tional medicine uses many plant products to treat diseaseshowever the exact mechanisms behind their use is stillmostly lacking partially as a consequence of the pleiotropiceffect of the active compounds as detailed in this reviewNevertheless clarification of the molecular mechanism ofaction of such natural compounds already used in traditionalmedicine for quite some time will undoubtedly aid in theproduction of safe and cheap candidate medications to beused in the treatment of diseases including those appearingas a consequence of NLRP3 inflammasome-mediated IL-1120573overproduction
Competing Interests
The authors declare no conflict of interests
Acknowledgments
This work was supported by OTKA-K 109429 Szilvia Benkois a receiver of Lajos Szodoray Postdoctoral Fellowship andJanos Bolyai Postdoctoral Fellowship
References
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[2] G Meng F Zhang I Fuss A Kitani and W Strober ldquoA muta-tion in the Nlrp3 gene causing inflammasome hyperactivationpotentiates Th17 cell-dominant immune responsesrdquo Immunityvol 30 no 6 pp 860ndash874 2009
[3] D Lasiglie E Traggiai S Federici et al ldquoRole of IL-1 beta in thedevelopment of human TH17 cells lesson fromNLPR3mutatedpatientsrdquo PLoS ONE vol 6 no 5 Article ID e20014 2011
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[5] E Gabay G Wolf Y Shavit R Yirmiya and M Tal ldquoChronicblockade of interleukin-1 (IL-1) prevents and attenuates neuro-pathic pain behavior and spontaneous ectopic neuronal activityfollowing nerve injuryrdquo European Journal of Pain vol 15 no 3pp 242ndash248 2011
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14 Mediators of Inflammation
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[73] S J Yang and Y Lim ldquoResveratrol ameliorates hepaticmetaflammation and inhibits NLRP3 inflammasome activa-tionrdquoMetabolism vol 63 no 5 pp 693ndash701 2014
[74] D-M Sui Q Xie W-J Yi et al ldquoResveratrol protects againstsepsis-associated encephalopathy and inhibits the NLRP3IL-1 120573 axis in microgliardquo Mediators of Inflammation vol 2016Article ID 1045657 10 pages 2016
[75] J Wu X Li G Zhu Y Zhang M He and J Zhang ldquoTherole of Resveratrol-inducedmitophagyautophagy in peritonealmesothelial cells inflammatory injury via NLRP3 inflamma-some activation triggered bymitochondrial ROSrdquoExperimentalCell Research vol 341 no 1 pp 42ndash53 2016
[76] Y W An K A Jhang S Y Woo J L Kang and Y HChong ldquoSulforaphane exerts its anti-inflammatory effectagainst amyloid-120573 peptide via STAT-1 dephosphorylationand activation of Nrf2HO-1 cascade in human THP-1macrophagesrdquo Neurobiology of Aging vol 38 pp 1ndash10 2016
[77] G Yang H E Lee and J Y Lee ldquoA pharmacological inhibitorof NLRP3 inflammasome prevents non-alcoholic fatty liver
Mediators of Inflammation 15
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[81] M Gold and J El Khoury ldquo120573-amyloid microglia andthe inflammasome in Alzheimerrsquos diseaserdquo Seminars inImmunopathology vol 37 no 6 pp 607ndash611 2015
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[84] X Dai K Sayama M Tohyama et al ldquoMite allergen is adanger signal for the skin via activation of inflammasome inkeratinocytesrdquo Journal of Allergy and Clinical Immunology vol127 no 3 pp 806ndash814 2011
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[86] B Vandanmagsar Y-H Youm A Ravussin et al ldquoThe NLRP3inflammasome instigates obesity-induced inflammation andinsulin resistancerdquo Nature Medicine vol 17 no 2 pp 179ndash1892011
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[88] L Liang X Tan Q Zhou et al ldquoIL-1120573 triggered by pepti-doglycan and lipopolysaccharide through TLR24 and ROS-NLRP3 inflammasome- dependent pathways is involved inocular behcetrsquos diseaserdquo Investigative Ophthalmology and VisualScience vol 54 no 1 pp 402ndash414 2013
[89] S Rosengren H M Hoffman W Bugbee and D L BoyleldquoExpression and regulation of cryopyrin and related proteinsin rheumatoid arthritis synoviumrdquo Annals of the RheumaticDiseases vol 64 no 5 pp 708ndash714 2005
[90] J M Kahlenberg ldquoAnti-inflammatory panaceaThe expandingtherapeutics of interleukin-1 blockaderdquo Current Opinion inRheumatology vol 28 no 3 pp 197ndash203 2016
[91] C-H Chien M-J Lee H-C Liou H-H Liou and W-MFu ldquoLocal immunosuppressive microenvironment enhancesmigration of melanoma cells to lungs in DJ-1 knockout micerdquoPLoS ONE vol 10 no 2 Article ID e0115827 2015
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[94] J H Hamman ldquoComposition and applications of Aloe vera leafgelrdquoMolecules vol 13 no 8 pp 1599ndash1616 2008
[95] L Langmead R J Makins and D S Rampton ldquoAnti-inflammatory effects of aloe vera gel in human colorectalmucosa in vitrordquo Alimentary Pharmacology and Therapeuticsvol 19 no 5 pp 521ndash527 2004
[96] N Yun C-H Lee and S-M Lee ldquoProtective effect of Aloe veraon polymicrobial sepsis inmicerdquo Food andChemical Toxicologyvol 47 no 6 pp 1341ndash1348 2009
[97] C S Yu F S Yu J K Chan et al ldquoAloe-emodin affects the levelsof cytokines and functions of leukocytes from Sprague-Dawleyratsrdquo In Vivo vol 20 no 4 pp 505ndash509 2006
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[99] Y-F Dong L-X Wang X Huang et al ldquoKir61 knock-down aggravates cerebral ischemiareperfusion-induced neuralinjury in micerdquo CNS Neuroscience and Therapeutics vol 19 no8 pp 617ndash624 2013
[100] P J Maier K Zemoura M A Acuna G E Yevenes HU Zeilhofer and D Benke ldquoIschemia-like oxygen and glu-cose deprivation mediates down-regulation of cell surface 120574-aminobutyric acidB receptors via the endoplasmic reticulum(ER) stress-induced transcription factor CCAATenhancer-binding protein (CEBP)-homologous protein (CHOP)rdquo TheJournal of Biological Chemistry vol 289 no 18 pp 12896ndash129072014
[101] H-Y Shin S-H Kim H-J Jeong et al ldquoEpigallocatechin-3-gallate inhibits secretion of TNF-120572 IL-6 and IL-8 through theattenuation of ERK and NF-120581B in HMC-1 cellsrdquo InternationalArchives of Allergy and Immunology vol 142 no 4 pp 335ndash3442007
[102] W P Pulskens L M Butter G J Teske et al ldquoNlrp3 preventsearly renal interstitial edema and vascular permeability inunilateral ureteral obstructionrdquo PLoS ONE vol 9 no 1 ArticleID e85775 2014
[103] S Kamath and C A Roobottom ldquoHyperdense pericardial effu-sion in dermatomyositis and contrast induced nephropathyrdquoEmergency Radiology vol 11 no 3 pp 177ndash179 2005
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[105] R Wang K C MoYung M H Zhang and K Poon ldquoUCP2-and non-UCP2-mediated electric current in eukaryotic cellsexhibits different propertiesrdquo Environmental Science and Pollu-tion Research vol 22 no 24 pp 19618ndash19631 2015
[106] J-M Lu Q Yao and C Chen ldquoGinseng compounds an updateon their molecular mechanisms and medical applicationsrdquoCurrent Vascular Pharmacology vol 7 no 3 pp 293ndash302 2009
[107] E Hernandez-Cuellar K Tsuchiya H Hara et al ldquoCuttingedge nitric oxide inhibits the NLRP3 inflammasomerdquo TheJournal of Immunology vol 189 no 11 pp 5113ndash5117 2012
[108] B B Mishra V A K Rathinam G W Martens et alldquoNitric oxide controls the immunopathology of tuberculosis byinhibiting NLRP3 inflammasome-dependent processing of IL-1120573rdquo Nature Immunology vol 14 no 1 pp 52ndash60 2013
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16 Mediators of Inflammation
[110] X Zhang J-H Zhang X-Y Chen et al ldquoReactive oxy-gen species-induced TXNIP drives fructose-mediated hepaticinflammation and lipid accumulation through NLRP3 inflam-masome activationrdquo Antioxidants and Redox Signaling vol 22no 10 pp 848ndash870 2015
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[112] H Inoue and R Nakata ldquoResveratrol targets in inflammationrdquoEndocrineMetabolic and ImmuneDisordersmdashDrug Targets vol15 no 3 pp 186ndash195 2015
[113] S S Kulkarni and C Canto ldquoThe molecular targets of resver-atrolrdquo Biochimica et Biophysica Acta (BBA)mdashMolecular Basis ofDisease vol 1852 no 6 pp 1114ndash1123 2015
[114] C A Houghton R G Fassett and J S Coombes ldquoSul-foraphane translational research from laboratory bench toclinicrdquo Nutrition Reviews vol 71 no 11 pp 709ndash726 2013
[115] A T Dinkova-Kostova W D Holtzclaw R N Cole et alldquoDirect evidence that sulfhydryl groups of Keap1 are the sensorsregulating induction of phase 2 enzymes that protect againstcarcinogens and oxidantsrdquo Proceedings of the National Academyof Sciences of the United States of America vol 99 no 18 pp11908ndash11913 2002
[116] E Heiss C Herhaus K Klimo H Bartsch and C GerhauserldquoNuclear factor 120581B is a molecular target for sulforaphane-mediated anti-inflammatory mechanismsrdquo The Journal of Bio-logical Chemistry vol 276 no 34 pp 32008ndash32015 2001
[117] A Alfieri S Srivastava R C M Siow et al ldquoSulforaphanepreconditioning of the Nrf2HO-1 defense pathway protectsthe cerebral vasculature against blood-brain barrier disruptionand neurological deficits in strokerdquo Free Radical Biology andMedicine vol 65 pp 1012ndash1022 2013
[118] C Lee G H Park S-R Lee and J-H Jang ldquoAttenuation of120573 -amyloid-induced oxidative cell death by sulforaphane viaactivation of NF-E2-related factor 2rdquo Oxidative Medicine andCellular Longevity vol 2013 Article ID 313510 12 pages 2013
[119] E Barrajon-Catalan M Herranz-Lopez J Joven et al ldquoMolec-ular promiscuity of plant polyphenols in the management ofage-related diseases far beyond their antioxidant propertiesrdquoAdvances in Experimental Medicine and Biology vol 824 pp141ndash159 2014
[120] L Bravo ldquoPolyphenols chemistry dietary sources metabolismand nutritional significancerdquo Nutrition Reviews vol 56 no 11pp 317ndash333 1998
[121] D W Lamming J G Wood and D A Sinclair ldquoSmallmolecules that regulate lifespan evidence for xenohormesisrdquoMolecular Microbiology vol 53 no 4 pp 1003ndash1009 2004
[122] K T Howitz and D A Sinclair ldquoXenohormesis sensing thechemical cues of other speciesrdquo Cell vol 133 no 3 pp 387ndash3912008
[123] P L Hooper P L Hooper M Tytell and L Vıgh ldquoXeno-hormesis health benefits from an eon of plant stress responseevolutionrdquoCell Stress and Chaperones vol 15 no 6 pp 761ndash7702010
[124] B L Queen and T O Tollefsbol ldquoPolyphenols and agingrdquoCurrent Aging Science vol 3 no 1 pp 34ndash42 2010
[125] J A Baur and D A Sinclair ldquoTherapeutic potential of resvera-trol the in vivo evidencerdquo Nature Reviews Drug Discovery vol5 no 6 pp 493ndash506 2006
[126] R A Sharma A J Gescher and W P Steward ldquoCurcumin thestory so farrdquoEuropean Journal of Cancer vol 41 no 13 pp 1955ndash1968 2005
[127] K Milton ldquoMicronutrient intakes of wild primates are humansdifferentrdquo Comparative Biochemistry and Physiology Part AMolecular amp Integrative Physiology vol 136 no 1 pp 47ndash592003
[16 82] NLRP3 inflammasome has also been related toallergic responses to a variety of allergens such as aluminumdust mite or ragweed pollen however the molecular detailsof these responses are still not clear [83ndash85]
Other studies associated NLRP3 inflammasome functionwithmetabolic syndrome and type 2 diabetes as NLRP3 defi-cient mice were protected from high fat diet- (HFT-) inducedinflammation glucose intolerance insulin resistance andobesity [86 87]
The dysregulated production of IL-1120573 by the NLRP3inflammasome is the main reason for the development ofCryopyrin-Associated Periodic Syndromes (CAPS) which iscaused by a mutation in NLRP3 gene CAPS is an autoin-flammatory disorder rather than an autoimmune one assymptoms aremediated by the innate immune systemmainlyby monocytes and macrophages that produce huge amountof IL-1120573 Behcetrsquos disease (BD) is another chronic autoin-flammatory disorder of unknown etiology and increasedIL-1120573 production has been noted as a central player in thepathogenesis of this disease Studies demonstrated increasedROS production and consequently increased NLRP3 func-tion in these patients suggesting an important role forNLRP3inflammasome in mediating cytokine production [88] Inaddition to autoinflammatory diseases NLRP3 inflamma-some function has also been implicated in the developmentof autoimmune diseases like rheumatoid arthritis (RA) [89]RA is a common inflammatory disease affecting small jointsand our knowledge about its pathogenesis is still incompleteNevertheless elevated levels of IL-1120573 and high expression ofNLRP3 were detected from the serum and synovial tissue aswell as in macrophages of RA patients [90]
At present the role of NLRP3 inflammasome and IL-1120573 in cancer is highly controversial The microenvironmentof tumors is characterized by an inflammatory milieu thathelps tumor survival with growth hormones endothelialactivation and angiogenesis that leads to metastasis accom-panied by immune suppression IL-1120573 participates in each ofthese mechanisms by stimulating the expression of TNF120572MMPs VEGF ICAM-1 VCAM and so forth Cancer cellslike melanoma or myeloma as well as tumor-associatedmacrophages and dendritic cells were shown to contribute tothe IL-1120573 production that helps survival and growth of tumorcells furthermore excessive production of IL-1120573 can recruitimmunosuppressive cells like myeloid-derived suppressorscells (MDSCs) [91] On the other hand it was also shown thatNLRP3-induced IL-1120573 production boosts T cell function inpatients receiving chemotherapy [92]
The classical medical approach to treating the above-mentioned diseases involves the use of synthetic drugs devel-oped against individual elements of the signaling pathwaythe IL-1120573 cytokine or the IL-1120573 receptor as reviewed inOzaki et al 2015 [93] However today in the health-cautiouslife era the use of botanical and natural compounds hasgained popularity While a few decades ago the use of naturalcompounds was based exclusively on empirical experiencestoday with the highly developed molecular biological highthroughput methods many molecular elements of theiraction have already been identified However fundamentalquestions remain to be answered including bioavailability
effective doses body concentrations cross-reactivity half-life and degradation and synergistic effect of compoundsas well as carefully designed clinical trials The aim of thepresent review is to provide an overview of these plant-derived natural compounds that would support the use ofmedicinal plants (Figure 2) As a variety of compounds caninfluence inflammasome activation and function we havefocused on natural compounds that have been in long termuse in traditional medicine therefore their safety and overalleffect are mostly established However these compoundstypically influence a multitude of pathways and the exactmolecular mechanisms of their beneficial actions are notcompletely clarified (Table 1)
41 Aloe vera Aloe vera is a medical plant used traditionallyin diverse therapeutic applications The gel of Aloe verahas been reported to stimulate wound-healing and skinhydration induce hematopoiesis and possess antidiabeticanticarcinogenic antimicrobial and antioxidant as well asanti-inflammatory activities Over 75 active components havealready been identified in Aloe vera leaf gels [94] andsome of them have been implicated as immunomodulatorycompounds based on animal studies In amouse sepsismodeland in a human colorectal mucosa model treatment withAloe vera significantly inhibited the elevation of TNF120572 IL-6 and IL-1120573 levels [95 96] Studying human THP-1 cellsand human monocyte-derived macrophages it was foundthat Aloe vera treatment significantly reduced LPS-inducedIL-1120573 production [51] Aloe vera inhibited the expressionof pro-IL-1120573 NLRP3 and caspase-1 as well as that of theP2X7 receptor in the LPS-induced primary macrophagesFurthermore LPS-induced activation of signaling pathwayssuch as NF-120581B p38 JNK and ERK were inhibited by Aloevera in these cells [51]
Aloe emodin is an anthraquinone present naturally inAloe leaves It has been shown to promote natural killer cellactivity andmacrophage phagocytosis in tumor [97] Emodinitself appears to have some protective effect in the inflamma-tory response Recently it was shown that emodin attenuatednigericin- ATP- and silica-induced IL-1120573 secretion fromLPS-activated murine bone marrow-derived macrophages(BMDMs) It was also shown that mice treated intraperi-toneally with emodin showed higher survival rates than con-trol mice injected with LPS alone indicating that emodin canameliorate the severity of NLRP3 inflammasome-mediateddisease symptoms in vivo [52] However further moleculardetails of the inhibitory effect are yet to be discovered
42 Curcumin Curcumin is a lipid soluble polyphenol ayellow pigment isolated from the rhizomes of Curcuma longa(turmeric) but also found in other plants like ginger It iswidely used in food coloring and flavoring and it is also addedto cosmetics It has gained attention in recent years for itsmultiple pharmacological properties being antioxidant anti-inflammatory and antimicrobial as well as for its therapeutic
Mediators of Inflammation 5
O
O
OHOH
OH
Emodin
O O
OHHO
Curcumin
O
O
HO
OH
OH
OH
OHQuercetin
O
SN
CS
Sulforaphane
O
OH
OH
HHO
Genipin
O
O
O
OH
OH
OH
HO
OH
OH
OH
EGCG
O
O
O OH
OH
OH
OH
HO
HO
HOMangiferin
OH
OH
OH
OH
OGlc
OGlcGinsenoside
(basic)
OH
OH
OH
HO
OH
HO
Resveratrol
trans- cis-
H3C
H3CO
OCH3
OCH3
CH3
Figure 2 Chemical structure of natural compounds influencing NLRP3 inflammasome activation
potential in cancer autoimmune metabolic pulmonarycardiovascular and neurological diseases (reviewed in [98])
Brain ischemia is known to induce ER stress and inflam-matory responses leading to neuronal damage [99 100] Ina recent study glucose deprivation or hypoxia was reportedto strongly induce the production of glutamate and IL-1120573 inmouse hippocampus [53] It was shown that pretreatmentof the mouse hippocampus with curcumin reduced IL-1120573 production and this effect was attenuated by 51015840-AMP-activated protein kinase (AMPK) inhibitor suggesting thepossible involvement of AMPK The authors also foundthat curcumin attenuated glutamate-induced phosphoryla-tion of PERK and IRE1120572 the transmembrane sensors ofER stress that mediate inflammatory signals Moreoverusing a neuroblastoma cell line they showed that curcumininhibited glutamate-induced ROS generation as well asreduced glutamate-induced TXNIP expression As a possiblemolecular mechanism they found that in mice hippocam-pus glutamate stimulation increased NLRP3 expression andthe cleaved form of caspase-1 enzyme while curcuminattenuated NLRP3 and cleaved caspase-1 expression Theproduction of IL-6 a downstream target of IL-1120573 was alsoinhibited by curcumin treatment In addition curcumineffectively attenuated mitochondrial function and preventedcaspase-3 activation in hippocampus exposed to glutamate
stimulation effectively preventing glutamate-induced cellapoptosis Furthermore in rats curcumin administrationattenuated ischemic brain injury resulting from middlecerebral artery occlusion (MCAO) Based on these findingscurcumin activates AMPK that inhibits glutamate-inducedER stress and ROS production thus inhibiting TXNIP-induced NLRP3 inflammasome activation and ultimatelyreducing IL-1120573 production in mouse hippocampus limitingbrain injury
Macrophages are popular models for the study ofNLRP3 inflammasome activation In another study per-formed on mouse macrophage cell line J774A1 and peri-toneal macrophages curcumin was shown to strongly inhibitIL-1120573 secretion triggered by LPS plus nigericin aluminumATP or MSU [54] Preincubation with curcumin preventednigericin-induced intracellular potassium level decreaseattenuated lysosome damage and cathepsin B leakage andblocked high mobility group box 1 (HMGB-1) release need-less to say all of these are components that may induceNLRP3 inflammasome activation In BMDMs curcumininhibited nigericin- or aluminum crystal-induced ROS pro-duction The authors did not find obvious inhibitory effectof curcumin on JNK and p38 phosphorylation enhancedby nigericin treatment in the LPS-primed macrophageshowever they found that ERK12 phosphorylation was
6 Mediators of Inflammation
Table 1 Natural compounds effecting NLRP3 inflammasome-mediated IL-1 production
Compound Effect Mechanism Target cell Reference
Aloe vera extract Reduced IL-1120573
Reduced expression of NLRP3procaspase-1 and P2X7RInhibition of ERK p38 NF120581Bsignaling
THP-1 and human MF [51]
Aloe emodin Reduced IL-1120573 Reduced expression of NLRP3procaspase-1 and ASC expression BMDM [52]
Aloe emodin Enhanced survival NLRP3-KO mice model of septicshock [52]
Curcumin Reduced IL-1120573 andcaspase-1 inhibition Reduced ER stress through AMPK Mouse hippocampus [53]
Curcumin Reduced ROS and TXNIP expression Neuroblastoma cells [53]
Reduced expression of NLRP3 ASCand caspase-1Reduced ROS and reducedmitochondrial dysfunctionActivation of AMPK and autophagy
Murine hepatocytes [77]
dramatically downregulated In a mouse model of LPS-induced septic shock administration of curcumin signif-icantly decreased ROS level and cathepsin B leakage inperitoneal macrophages additionally peritoneal HMGB-1and IL-1120573 concentrations were downregulated resulting ina reduced LPS-induced splenomegaly These data suggestthat the observed reduction of secreted mature IL-1120573 bycurcumin is primarily attributed to the inhibition of NLRP3inflammasome activation
43 EGCG Epigallocatechin-3-gallate (EGCG) is the majorbioactive polyphenol in green tea that has a well-documentedantioxidant activity as it functions as a free-radical scavengerEGCG was reported to inhibit NF120581B activation and thesubsequent expression of several inflammatory moleculessuch as inducible nitric oxide synthase (iNOS) matrixmetalloproteinases (MMPs) IL-6 and TNF120572 Besides theanti-inflammatory role EGCG was also thought to possessantitumor effect [101]
In unilateral ureteral obstruction mice model renalinflammation has been linked to the activity of NLRP3inflammasome and the overproduction of IL-1120573 Further-more the role of NLRP3 inflammasome was proven in a vari-ety of human nondiabetic and chronic kidney diseases [102]It was reported that EGCG can prevent the development of
lupus nephritis when administered to NZBW F1 mice theclassical model of systemic lupus erythematosus [55] Thesestudies showed that EGCG treatment activated Nrf2 antiox-idant pathway induced the expression of Nrf2 downstreamenzymes like NAD(P)H dehydrogenase (quinone) 1 (NQO1)and heme oxygenase 1 (HO-1) and reduced renal oxidativestress Furthermore EGCG inhibited renal NLRP3 inflam-masome activity and the expressions of NLRP3 caspase-1and IL-1120573 were also reduced possibly due to the EGCG-induced attenuation of NF120581B pathway activity
Very recently the beneficial effect of EGCG was reportedin a contrast-inducednephropathy (CIN) ratmodel [56] CINis a common iatrogenic cause of acute kidney injury (AKI)after exposure to iodinated contrast medium characterizedby oxidative stress and inflammation [103] Similar to theprevious study they found that EGCG treatment reducedoxidative stress and increased Nrf2 and HO-1 expressionThey also found that EGCG reduced the elevated IL-1120573secretion and NLRP3 protein expression The molecularmechanisms of the observed results however were notstudied
44 Genipin Genipin is a water-soluble bifunctional cross-linking reagent that was initially isolated from the Chinesemedicinal plant Gardenia jasminoides (common name jas-mine) and it has been used for centuries as a herbal medicine
8 Mediators of Inflammation
to protect the liver and gallbladder It possesses antihyper-tensive antibleeding and antiswelling properties in additionto exhibiting anti-inflammatory characteristics Chemicallyit is an aglycone derived from an iridoid glycoside calledgeniposide that is enzymatically hydrolyzed to genipin byintestinal bacteria when administered per os [104] Genipinwas reported to inhibit mitochondrial uncoupling protein2 (UCP2) as well as superoxide-activated UCP2-mediatedproton leak occurring in a variety of diseases [105]
Recently it was shown that overexpression of UCP2caused a significant increase in NLRP3 expression in THP-1 cells and this was significantly inhibited by the adminis-tration of genipin while the levels of the adaptor proteinASC did not change [57] Interestingly genipin treatmentattenuated IL-1120573 levels in LPS-primed cells treated with ATPhowever this effect was not observed in cells treated withnigericin In addition it was also shown that inhibition ofATP-mediated inflammasome activation by genipin does notalter the production of other proinflammatory cytokines suchas IL-6 and TNF120572
In another recent study in LPS-primed murine BMDMsgenipin dramatically inhibited IL-1120573 secretion of LPS-primedcells following ATP nigericin MSU crystals or Listeriamonocytogenes treatment [58] Furthermore genipin alsoinhibited the Salmonella typhimurium-induced secretion ofIL-1120573 which is mediated via the activation of NLRC4inflammasome Similar to the previous study LPS-dependentTNF120572 secretion was not impaired by genipin Importantlygenipin treatment did not inhibit the expression of pro-IL-1120573 pro-caspase-1 or ASC proteins however it inhibitedNLRP3-dependent ASC oligomerization in addition to IL-1120573secretion and caspase-1 activation In contrast to its inhibitoryeffect on NLRP3-mediated ASC oligomerization genipindid not affect NLRC4-mediated formation of ASC speckleswhileNLRC4-mediated caspase-1 activationwas significantlydiminished These data indicate that the inhibitory effect ofgenipin on NLRC4 inflammasome activation is independentof ASC
45 Ginseng White ginseng is the naturally dried formof ginseng (Panax ginseng) while red ginseng is made bysteaming and drying fresh ginseng root Red ginseng hasbeen used for centuries as an immune-modulator and hasalso been used as an adjuvant in the treatment of infectiousand metabolic diseases Korean red ginseng contains variousactive components including saponins such as ginsenosidesand nonsaponins such as polysaccharides peptides fattyacids and mineral oils Ginsenosides are the major activecomponents of ginseng They reduce the production ofinflammatory cytokines by inhibiting NF120581B signaling [106]They also have amphiphilic nature and are able to intercalateinto the plasma membrane and influence membrane fluidityand function
It was shown that red ginseng extract (RGE) inhibitedATP- nigericin- and aluminum-induced IL-1120573 secretionin LPS-primed BMDMs and THP-1 cells and amelioratedlethality in LPS-induced septic shock model of mice [59]Furthermore RGE attenuated IL-1120573 secretion in dsDNA-transfected macrophages Similar results were obtained for
ginsenosides Furthermore it was also shown that RGE actedas an inhibitor of both NLRP3 and AIM2 inflammasomeactivations It was also demonstrated that RGE attenuated thesecretion of the active form of caspase-1 (p20)
It was previously reported that endogenousNOproducedby iNOS inhibits NLRP3 inflammasome activation via theS-nitrosylation of NLRP3 protein [107 108] A recent studyreported that ginsenosides negatively regulates LPS-inducedseptic shock in mice by a mechanism involving inhibitionof iNOS expression and the subsequent NO production[60] It was shown that ginsenosides reduced NO leveliNOS expression and ROS level in peritoneal macrophagesand BMDMs after LPS stimulation They also found thatginsenoside treatment attenuated S-nitrosylation of NLRP3protein which resulted in increased IL-beta secretion in LPS-activated macrophages
46 Mangiferin Mangiferin is a water-soluble naturalpolyphenol with a C-glycosylxanthone structure The pri-mary source of mangiferin is the mango tree (Mangiferaindica) however it is also present in some medicinal herbsin Iris unguicularis and in the honeybush a popular herbaltea from South Africa It possesses a wide spectrum ofbeneficial effects on health being used as an analgesicantidiabetic antisclerotic antimicrobial and antiviral as wellas being praised for its anti-inflammatory effects It has beenshown to regulate AMPK activity and in a recent work itwas reported that in human endothelial cells exposed tohigh glucose mangiferin reduced IL-1120573 secretion [61] Fur-thermore mangiferin attenuated IRE1 phosphorylation andreducedROS production and it decreased TXNIP expressionand inhibited ER stress Moreover a decrease in NLRP3expression and IL-1120573 production was also demonstrated
Very recently the protective role of mangiferin wasdescribed in LPS plus D-galactosamine- (D-GalN-) inducedacute liver injury [62] The authors showed that mangiferinreduced IL-1120573 secretion and ROS production and it alsoinhibited iNOS expression but induced Nrf2 and HO-1expression Furthermore it attenuated NLRP3 ASC andcaspase-1 (p10) expression and the subsequent IL-1120573 produc-tion
47 Propolis Propolis is a resinous material produced bybees (Apis mellifera L) through the mixing of secretions andenzymes from their hypopharyngeal glands with the budsof plants and wax A few hundred compounds have beendetected in raw propolis including polyphenols terpenoidssteroids sugar and amino acids Propolis composition islargely influenced by botanical origins and geographicallocation as well as by collection season One of the mostknown biological activities of propolis is related to its anti-inflammatory effect Artepillin C is a simple phenol com-posed of a single ring with two prenyl groups (35-diprenyl-4-hydroxycinnamic acid) and is the major biologically activephenolic ingredient identified in green propolis derived fromSoutheast Brazil [109]
The role of artepillin C was studied on the oxidativemetabolism of PMA-stimulated RAW2647 macrophages[63] It was shown that artepillin C significantly inhibited
Mediators of Inflammation 9
ROS release upon the NLRP3 activator nigericin treatment Itwas also suggested that artepillin C significantly contributedto the modulation of chemokine-mediated inflammation asit significantly downregulated the release of IL-1120573 IL-12p40and TNF120572 by LPS + IFN120574-treated RAW2647 cells whereasthe synthesis of IL-1120572 and IL-6 was not affected Besidesnigericin-mediated IL-1120573 production propolis also inhibitedLegionella pneumophila-induced IL-1120573 cytokine secretionin LPS-primed BMDMs This indicates that both NLRP3and NLRC4 inflammasome functions may be regulated bypropolis however further studies are required to clarify thedetailed molecular mechanism of the observed results
48 Quercetin Quercetin a kind of flavonoid found in avariety of vegetables beverages fruits and herbs exhibitsanti-inflammatory and antioxidant properties Quercetinwasreported to reduce inflammation in visceral adipose tissueprimary human adipocytes and the kidney of fructose-fedrats It was also shown to prevent diabetic kidney injury inratsHowever themechanisms of the action of quercetinwerenot clarified
It has been described that quercetin attenuated fructose-induced hyperuricemia and renal dysfunction In a studyusing streptozotocin- (STZ-) induced diabetic nephropa-thy rat model leading to hyperuricemia and dyslipidemiaquercetin was found to block NLRP3 inflammasome acti-vation [64] It was shown that the STZ-induced expres-sion of inflammasome components was restrained and IL-1120573 secretion was reduced by quercetin treatment Similarresults were obtained studying inflammatory responses infructose-induced hyperuricemia in rat [65] They showedthat fructose significantly elevated the expression of renalNLRP3 ASC and caspase-1 expression while quercetintreatment ameliorated the expression of these proteins Basedon their findings it was suggested that fructose-mediatedrenal NLRP3 inflammasome activation and proinflamma-tory cytokine overproduction may be associated with theimpaired cross talk between renal JAK2-STAT3 and PPAR-120572signaling pathway that in turn regulate renal inflammation
Furthermore it was shown that quercetin markedlyinhibited the overexpression of hepatic TXNIP in additionto reducing the production of ROS and the activation ofNLRP3 inflammasome consequently resulting in decreasedIL-1120573 secretion [66 110]They also showed that the decreasedcaspase-1 activity downregulated the caspase-1-dependentactivation of SREBPs that are involved in fatty acid andcholesterol synthesis They suggested that regulation of theTXNIP-NLRP3-SREBPs pathway by quercetin may partiallymediate the alleviation of hepatic steatosis in these diabeticrats
It was also shown that quercetin treatment regulatedAMPK pathway activation glutamine-glutamate cycle dys-function and TXNIP overexpression moreover it sup-pressed NF120581B pathway eventually leading to impairedNLRP3 inflammasome activation and IL-1120573 production inthe hypothalamus of high fructose- (HF-) fed rats [67]
Using human umbilical vein endothelial cells anothergroup reported that quercetin suppressed palmitate- (PA-) induced IL-1120573 and IL-6 induction [68] Downregulation
of NLRP3 induction was probably partially mediated viathe inhibition of ROS production and TXNIP expressionquercetin also inhibited IKK120573 activation by attenuatingits phosphorylation Furthermore quercetin treatment pro-tected cells against PA insult and significantly reduced thenumber of apoptotic cells Moreover quercetin amelioratedER stress-induced endothelial dysfunction through the acti-vation of AMPK
NLRP3 inflammasome is also recognized to have animportant role in the spinal cord tissue after traumatic spinalcord injury (SCI) and targeting the NLRP3 inflammasomecan inhibit neuroinflammation thereby improving func-tional recovery in SCI rats [111]
Very recently in a ratmodel of SCI quercetin administra-tion was shown to significantly improve functional recovery[69] Histopathological changes of the spinal cord such ascongestion edema neutrophil infiltration and structuraldisruption were inhibited by quercetin administration Toformulate a molecular mechanism the authors showed thatquercetin administration significantly reduced inflammatorycytokine IL-1120573 IL-18 and TNF120572 levels it also reduced theNLRP3 ASC and active caspase-1 protein expression andROS production However further studies are needed tobetter characterize the mechanisms of action underlying thebeneficial effects of quercetin in inflammation and immunity
49 Resveratrol Resveratrol is a polyphenol present inthe skin of grapes and mulberry commonly used in redwine production The beneficial effects of resveratrol arethought to be mediated in part by its antioxidant andanti-inflammatory properties exhibiting beneficial effectsin several diseases [112] Resveratrol exists as two isomerscis- and trans-resveratrol The cis isomer is thought to beproduced naturally during grape fermentation as a resultof isomerization of the trans isomer by yeast isomerasesFurthermore cis-resveratrol can be obtained by exposure ofthe trans isomer to sunlight Several studies have shown thattrans-resveratrol exhibits a wide range of biological activitiesincluding anti-inflammatory antioxidant anticarcinogenicantiaging antiplatelet aggregation immune-modulatory andchemoprevention effects However only few studies havebeen performed to examine the biological effects of the cisisomer Studies on cis-resveratrol have demonstrated thatit also possesses anticancer antimicrobial and antiplateletaggregation activities
One of the biological roles of resveratrol is to initiate theactivation of sirtuin 1 (Sirt1) is a deacetylase that modifies andinactivates inflammatory genes At high doses resveratrolhas been shown to activate AMPK which is involved inthe negative regulation of the NLRP3-inflammasome [113]It was also shown that ionizing radiation-induced IL-1120573secretion by human mesenchymal stem cells (MSCs) aneffect that was effectively abrogated by pretreatment withresveratrol [70] Radiation-induced increase in IL-1120573 occursvia the NLRP3 inflammasome activation however resver-atrol treatment attenuated the expression of NLRP3 It wasalso demonstrated that resveratrol treatment upregulated theexpression of Sirt1 In conclusion it is suggested that Sirt1
10 Mediators of Inflammation
inhibits NF120581B transcriptional activity through deacetylationthat in turn limits the transcription of NLRP3
In another study it was shown that cis-resveratrol pre-treatment significantly inhibited IL-1120573 secretion in THP-1 cellculture supernatants interestingly cis-resveratrol inducedIL-18 secretion under these conditions [71] Accordingly cis-resveratrol significantly reduced IL-1120573 mRNA expressionin contrast cis-resveratrol used at the same concentra-tion increased IL-18 mRNA expression Furthermore cis-resveratrol increased the mRNA and protein levels of NLRP1and NLRP3 indicating that the inhibitory effect of cis-resveratrol on IL-1120573 secretion is not due to the down-regulation of NLRP1 NLRP3 or ASC expression Similarresults were obtained on LPS-primed J774A1 macrophageswhere resveratrol inhibited the ATP-induced IL-1120573 secretionhowever in this study the authors did not find changes in theexpression of NLRP3 [72] showing that the resveratrol didnot inhibit the priming signal of NLRP3
Huang et al suggested that the inhibitory effect of cis-resveratrol on IL-1120573 secretion may be due to the reducedexpression of purinergic receptor P2X7R and the ER stressmarker GRP78 which leads to suppression of ROS pro-duction and reduced caspase-1 and caspase-4 activation Itwas found that cis-resveratrol also inhibited cyclooxygenase-(COX-) 2 expression which may be responsible for theobserved decrease of PGE2 production Furthermore inhi-bition of pro-IL-1120573 and COX-2 expression may occur bydownregulating the activation of the p38 MAPK path-way [71] Importantly in contrast to these observationsincreased phosphorylation of p38 was detected in ATP-activated J774A1 macrophages by Chang et al while itdid not significantly increase the phosphorylation levelsof ERK12 and it reduced the phosphorylation levels ofJNK12 The levels of mtDNA release into the cytosol weresignificantly reduced by resveratrol indicating that therewas less mitochondrial injury in resveratrol-treated cells[72] Furthermore the authors also showed that resveratrolincreased cellular cAMP level in J774A1 macrophages whichacts as a negative regulator of inflammatory responses andinhibits NLRP3 inflammasome activation
The effect of resveratrol on NLRP3 inflammasome wasfurther proved by a study showing that four weeks ofresveratrol administration inhibited the expression of NLRP3inflammasome components IL-1 IL-6 and TNF120572 and inlivers of HF-fed mice [73] They also showed that theregulatory effects of resveratrol on NLRP3 inflammasomemay come about through the combined effects of Sirt1 andSirt6
In a recent study [50] it was found that resveratroltreatment successfully suppressed the maturation of bothIL-1120573 and caspase-1 in response to Pam3CSK4 a TLR12agonist plus various inducers (like nigericin ATP MSUand silica) of the NLRP3-inflammasome In mouse BMDMshowever it did not affect the production of IL-1120573 medi-ated by the NLRC4-inflammasome (flagellin) or the AIM2-inflammasome (dsDNA) On a mouse model of acute goutthey indicated that resveratrol reduced the amount of matureIL-1120573 and the subsequent recruitment of neutrophils intothe peritoneal cavities of mice after challenge with MSU
crystals These findings indicate that resveratrol suppressesthe activation of the NLRP3-inflammasome both in vitroand in vivo As a possible mechanism they showed thatresveratrol at a substantially higher dosage successfullysuppressed mitochondrial ROS production Furthermoreresveratrol treatment prevented the accumulation of acety-lated 120572-tubulin thusinhibiting the proximate localization ofASC and NLRP3 in macrophages
In a very recent publication [74] the authors showed thatresveratrol preventedATP-inducedNLRP3 activation and IL-1120573 production in the BV2 cell line and in septic mice as wellThey also found that resveratrol treatment reduced NLRP3and IL-1120573 expression in the hippocampus of the mice andthey suggested that the protecting effect of resveratrol wasmediated via the increased expression of Sirt1 in BV2 cells
Another recent publication found that glucose-basedperitoneal dialysis increased mitochondrial ROS productionand subsequent IL-1120573 secretion through NLRP3 inflamma-some in human peritoneal mesothelial cells (HPMC) Asa mechanism for its action they showed that resveratrolinduced mitophagyautophagy of the cells via AMPK activa-tion and protected cells fromROS-inducedNLRP3-mediatedinflammatory injury [75]
410 Sulforaphane Sulforaphane (SFN) is a natural com-pound present in cruciferous vegetables such as broccolicabbage Brussel sprouts mustard and radish ChemicallySFN is an isothiocyanate that is known to react withsulfhydryl groups and tomodify proteins at cysteine residuesSulforaphane is produced from the precursor glucoraphaninby the enzymatic activity of myrosinase when the cell wallsof the plant are damaged for example during chewingSFN has been known as a cytoprotective agent for cancerprevention or treatment and it also has an important rolein cardiovascular neurologic and other diseases (reviewedin [114]) SFN is a known inducer of the Nrf2 antioxidantpathway as it activates the Nrf2 transcription factor byreacting with cysteine residues of its repressor Keap1 [115]In addition it also inhibits NF120581B signaling [116]
It was shown that SFN inhibited IL-1120573 processing byNLRP1- NLRP3- NLRC4- and AIM2- inflammasome com-plexes in mouse BMDMs [28] It was also demonstratedthat SFN inhibits the inflammasome in an Nrf2-independentmanner as SFN-mediated inhibition of NLRP3- andNLRC4-dependent IL-1120573 processing and secretion was not reversedin Nrf2-knockout BMDMs When SFN was added directlyto the cell lysates it did not inhibit IL-1120573 processingdemonstrating that SFN does not directly inhibit the proteaseactivity of caspase-1 The authors found that SFN-mediatedinhibition of the inflammasomes is not affected by ROSmodulation and neither proteasome-dependent proteolysisnor de novo protein synthesis is required for SFN-mediatedinhibition of the inflammasomes In a peritonitis model ofacute gout SFN treatment significantly reducedMSU crystal-induced IL-1120573 production demonstrating that SFN inhibitsthe NLRP3 inflammasome function in vivo Nonethelessthe authors concluded that SFN inhibits multiple inflam-masomes in vitro and in vivo by a mechanism independent
Mediators of Inflammation 11
ERKp38
NLRP3
ASCNLRP3
Caspase-1ROS
ER stress
P2X7R ATP
Cathepsin B
TLR
ROS
mtDNA
Sirt2
AcAc
AcAc
AMPK
A
A AC
C
C
Nrf2E
E
UCP2Ge
Ge
Ge
Gi
TXNIPC
NOGi
P
Sirt1R
R
R
R
M
M
M
Q
QQ
SS
S
R
Cardio-lipin
Acetylated 120572-tubulin
Ca2+ influx
IL-1120573
Pro-IL-1120573
K+efflux
120572-Tubulin
Pro-IL-1120573
NF120581B
Figure 3 Molecular targets of natural compounds affecting NLRP3 inflammasome-mediated IL-1 production
of inflammasome priming and Nrf2 signaling however theexact molecular mechanism was not explored
As SFN is able to penetrate the blood-brain barrier[117] it gained a considerable attention as a candidatefor Alzheimerrsquos disease (AD) therapy SFN was shown toprotect the brain from A120573-induced oxidative cell death viaactivation of Nrf2 signaling cascade [118] As A120573 fibrilshave been shown to activate NLRP3 inflammasome thequestion arose whether SFN may regulate this mechanismIn a very recent study it was shown that SFN significantlydownregulated IL-1120573 production and NLRP3 expression inA1205731ndash42 peptide-stimulated human THP-1 cells macrophages[76] It was found that A1205731ndash42 peptide-induced STAT-1phosphorylation was significantly attenuated by SFN Theauthors showed that SFN inducedNrf2 nuclear translocationwhich was subsequently accompanied by an increase in HO-1 protein levels Furthermore A1205731ndash42 peptide-induced IL-1120573 production was diminished by siRNA-mediated knock-down of Nrf2 or HO-1 They also found that the increasedproinflammatory miRNA-146a level following A1205731ndash42 treat-ment was significantly attenuated by SFN whereas miRNA-125b and miRNA-155 levels were not changed These arespecific proinflammatory miRNAs that were reported to beincreased in both the extracellular fluid and cerebrospinalfluid of AD patients In conclusion SFN can suppress A1205731ndash42-induced caspase-1-dependent inflammasome activationpossibly through inhibiting STAT-1 phosphorylation andactivation of the Nrf2HO-1 signaling pathway
Also very recently another research group reported thatoral administrations of SFN suppressed the saturated fattyacid-induced NLRP3 inflammasome activation in the liverof mice [77] They found that SFN decreased the expression
of ASC caspase-1 and IL-1120573 levels additionally it inhibitedthe activity of caspase-1 enzyme in primary hepatocytes Itwas also shown that SFN reduced the palmitate-inducedROS production by the mitochondria implying that SFNprevented mitochondrial dysfunction and this protectingmechanism was in part mediated by the activation of AMPKThey concluded that activation of AMPK and autophagy bySFN could protect from mitochondrial dysfunction inducedby saturated fatty acids resulting in a downregulation of fat-induced activation of the NLRP3 inflammasome
5 NLRP3 Inflammasome and theXenohormesis Hypothesis
As it was described in detail above polyphenols like resvera-trol curcumin EGCG and quercetin are potent inhibitors ofNLRP3 inflammasome-mediated IL-1120573 production typicallyacting at more than one element of the involved pathways(Figure 3)However it should be noted that these polyphenolshave an evenmuch broader biological effect as they influencea variety of pathways [119] though not all are directlyconnected to the function of the NLRP3 inflammasomeImportantly more than 8000 natural polyphenols have beendescribed [120] providing a large library of compounds aspotential inflammasome inhibitors Many of these polyphe-nols (such as resveratrol and curcumin) are overproducedby stressed plants triggering pathways mimicking the effectof caloric restriction It has been proposed that organismsfrom yeast to humans consuming stressed plants couldinterpret the stress signal carried by such polyphenols as apotential risk of future limitation of food availability and in
12 Mediators of Inflammation
turn adapting for the pursuit of longevity a theory termedas Xenohormesis [121ndash123] Interestingly the structurallyunrelated resveratrol and curcumin can achieve this caloricrestriction mimicking effect by activating AMPK and Sirt1[124] However polyphenols are also known to have anantioxidant effect activate glutathione S-transferases andinhibit COX enzymes among many other effects [125 126]Interestingly one of the most frequently used COX inhibitoris aspirin a derivative of another stress-induced phytochem-ical salicylic acid
A major concern of polyphenol use in therapy is thebioavailability of these compounds Nevertheless typicaldietary polyphenol intake is about 14mgkgday which iswithin the range of providing biologically active doses [127]
6 Concluding Remarks
Most of the time inflammasome-mediated IL-1120573 productionor caspase-mediated pyroptosis is beneficial for the host as itprotects from infection or prevents further damageHoweverprolonged cytokine production as in the case of sterileinflammation caused by endogenous danger signals maylead to the development of autoinflammatory or metabolicdiseases Chronic inflammation compromises the hostrsquos lifequality and requires sustained pharmacological and surgicaltreatments The paradigm of drug discovery in Westernmedicine is to develop highly selective compounds againstindividual druggable targets Currently the main treatmentmethods for these patients are targeting IL-1120573 Howeverprolonged usage of drugs may induce different side effectsfurthermore some form of medications are very expensivewhich limits their widespread use
Besides the high expenses another drawback of tradi-tional drug design is that many of the promising compoundsfail in the early or later stages of drug development Tradi-tional medicine uses many plant products to treat diseaseshowever the exact mechanisms behind their use is stillmostly lacking partially as a consequence of the pleiotropiceffect of the active compounds as detailed in this reviewNevertheless clarification of the molecular mechanism ofaction of such natural compounds already used in traditionalmedicine for quite some time will undoubtedly aid in theproduction of safe and cheap candidate medications to beused in the treatment of diseases including those appearingas a consequence of NLRP3 inflammasome-mediated IL-1120573overproduction
Competing Interests
The authors declare no conflict of interests
Acknowledgments
This work was supported by OTKA-K 109429 Szilvia Benkois a receiver of Lajos Szodoray Postdoctoral Fellowship andJanos Bolyai Postdoctoral Fellowship
References
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[2] G Meng F Zhang I Fuss A Kitani and W Strober ldquoA muta-tion in the Nlrp3 gene causing inflammasome hyperactivationpotentiates Th17 cell-dominant immune responsesrdquo Immunityvol 30 no 6 pp 860ndash874 2009
[3] D Lasiglie E Traggiai S Federici et al ldquoRole of IL-1 beta in thedevelopment of human TH17 cells lesson fromNLPR3mutatedpatientsrdquo PLoS ONE vol 6 no 5 Article ID e20014 2011
[4] H Schneider F Pitossi D Balschun A Wagner A Del Reyand H O Besedovsky ldquoA neuromodulatory role of interleukin-1120573 in the hippocampusrdquo Proceedings of the National Academy ofSciences of the United States of America vol 95 no 13 pp 7778ndash7783 1998
[5] E Gabay G Wolf Y Shavit R Yirmiya and M Tal ldquoChronicblockade of interleukin-1 (IL-1) prevents and attenuates neuro-pathic pain behavior and spontaneous ectopic neuronal activityfollowing nerve injuryrdquo European Journal of Pain vol 15 no 3pp 242ndash248 2011
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[47] N Subramanian K Natarajan M R Clatworthy Z Wangand R N Germain ldquoThe adaptor MAVS promotes NLRP3mitochondrial localization and inflammasome activationrdquo Cellvol 153 no 2 pp 348ndash361 2013
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14 Mediators of Inflammation
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[50] T Misawa M Takahama T Kozaki et al ldquoMicrotubule-drivenspatial arrangement ofmitochondria promotes activation of theNLRP3 inflammasomerdquo Nature Immunology vol 14 no 5 pp454ndash460 2013
[51] M M Budai A Varga S Milesz J Tozser and S BenkoldquoAloe vera downregulates LPS-induced inflammatory cytokineproduction and expression of NLRP3 inflammasome in humanmacrophagesrdquo Molecular Immunology vol 56 no 4 pp 471ndash479 2013
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[53] Y Li J Li S Li et al ldquoCurcumin attenuates glutamate neurotox-icity in the hippocampus by suppression of ER stress-associatedTXNIPNLRP3 inflammasome activation in a manner depen-dent onAMPKrdquoToxicology andApplied Pharmacology vol 286no 1 pp 53ndash63 2015
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[67] Q-Y Zhang Y Pan R Wang et al ldquoQuercetin inhibitsAMPKTXNIP activation and reduces inflammatory lesions toimprove insulin signaling defect in the hypothalamus of highfructose-fed ratsrdquo Journal of Nutritional Biochemistry vol 25no 4 pp 420ndash428 2014
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[69] W Jiang Y Huang N Han et al ldquoQuercetin suppresses NLRP3inflammasome activation and attenuates histopathology in a ratmodel of spinal cord injuryrdquo Spinal Cord vol 54 pp 592ndash5962016
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[71] T-T Huang H-C Lai Y-B Chen et al ldquoCis-Resveratrolproduces anti-inflammatory effects by inhibiting canonicaland non-canonical inflammasomes in macrophagesrdquo InnateImmunity vol 20 no 7 pp 735ndash750 2014
[72] Y-P Chang S-M Ka W-H Hsu et al ldquoResveratrol inhibitsNLRP3 inflammasome activation by preserving mitochondrialintegrity and augmenting autophagyrdquo Journal of Cellular Physi-ology vol 230 no 7 pp 1567ndash1579 2015
[73] S J Yang and Y Lim ldquoResveratrol ameliorates hepaticmetaflammation and inhibits NLRP3 inflammasome activa-tionrdquoMetabolism vol 63 no 5 pp 693ndash701 2014
[74] D-M Sui Q Xie W-J Yi et al ldquoResveratrol protects againstsepsis-associated encephalopathy and inhibits the NLRP3IL-1 120573 axis in microgliardquo Mediators of Inflammation vol 2016Article ID 1045657 10 pages 2016
[75] J Wu X Li G Zhu Y Zhang M He and J Zhang ldquoTherole of Resveratrol-inducedmitophagyautophagy in peritonealmesothelial cells inflammatory injury via NLRP3 inflamma-some activation triggered bymitochondrial ROSrdquoExperimentalCell Research vol 341 no 1 pp 42ndash53 2016
[76] Y W An K A Jhang S Y Woo J L Kang and Y HChong ldquoSulforaphane exerts its anti-inflammatory effectagainst amyloid-120573 peptide via STAT-1 dephosphorylationand activation of Nrf2HO-1 cascade in human THP-1macrophagesrdquo Neurobiology of Aging vol 38 pp 1ndash10 2016
[77] G Yang H E Lee and J Y Lee ldquoA pharmacological inhibitorof NLRP3 inflammasome prevents non-alcoholic fatty liver
Mediators of Inflammation 15
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[79] S L Cassel and F S Sutterwala ldquoSterile inflammatory responsesmediated by the NLRP3 inflammasomerdquo European Journal ofImmunology vol 40 no 3 pp 607ndash611 2010
[80] M-S Tan J-T Yu T Jiang X-C Zhu and L Tan ldquoThe NLRP3inflammasome in alzheimerrsquos diseaserdquoMolecular Neurobiologyvol 48 no 3 pp 875ndash882 2013
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[84] X Dai K Sayama M Tohyama et al ldquoMite allergen is adanger signal for the skin via activation of inflammasome inkeratinocytesrdquo Journal of Allergy and Clinical Immunology vol127 no 3 pp 806ndash814 2011
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[89] S Rosengren H M Hoffman W Bugbee and D L BoyleldquoExpression and regulation of cryopyrin and related proteinsin rheumatoid arthritis synoviumrdquo Annals of the RheumaticDiseases vol 64 no 5 pp 708ndash714 2005
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[91] C-H Chien M-J Lee H-C Liou H-H Liou and W-MFu ldquoLocal immunosuppressive microenvironment enhancesmigration of melanoma cells to lungs in DJ-1 knockout micerdquoPLoS ONE vol 10 no 2 Article ID e0115827 2015
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[95] L Langmead R J Makins and D S Rampton ldquoAnti-inflammatory effects of aloe vera gel in human colorectalmucosa in vitrordquo Alimentary Pharmacology and Therapeuticsvol 19 no 5 pp 521ndash527 2004
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[97] C S Yu F S Yu J K Chan et al ldquoAloe-emodin affects the levelsof cytokines and functions of leukocytes from Sprague-Dawleyratsrdquo In Vivo vol 20 no 4 pp 505ndash509 2006
[98] M Pulido-Moran J Moreno-Fernandez C Ramirez-Tortosaand M Ramirez-Tortosa ldquoCurcumin and healthrdquo Moleculesvol 21 no 3 article E264 2016
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[100] P J Maier K Zemoura M A Acuna G E Yevenes HU Zeilhofer and D Benke ldquoIschemia-like oxygen and glu-cose deprivation mediates down-regulation of cell surface 120574-aminobutyric acidB receptors via the endoplasmic reticulum(ER) stress-induced transcription factor CCAATenhancer-binding protein (CEBP)-homologous protein (CHOP)rdquo TheJournal of Biological Chemistry vol 289 no 18 pp 12896ndash129072014
[101] H-Y Shin S-H Kim H-J Jeong et al ldquoEpigallocatechin-3-gallate inhibits secretion of TNF-120572 IL-6 and IL-8 through theattenuation of ERK and NF-120581B in HMC-1 cellsrdquo InternationalArchives of Allergy and Immunology vol 142 no 4 pp 335ndash3442007
[102] W P Pulskens L M Butter G J Teske et al ldquoNlrp3 preventsearly renal interstitial edema and vascular permeability inunilateral ureteral obstructionrdquo PLoS ONE vol 9 no 1 ArticleID e85775 2014
[103] S Kamath and C A Roobottom ldquoHyperdense pericardial effu-sion in dermatomyositis and contrast induced nephropathyrdquoEmergency Radiology vol 11 no 3 pp 177ndash179 2005
[104] T Akao K Kobashi and M Aburada ldquoEnzymic studies onthe animal and intestinal bacterial metabolism of geniposiderdquoBiological and Pharmaceutical Bulletin vol 17 no 12 pp 1573ndash1576 1994
[105] R Wang K C MoYung M H Zhang and K Poon ldquoUCP2-and non-UCP2-mediated electric current in eukaryotic cellsexhibits different propertiesrdquo Environmental Science and Pollu-tion Research vol 22 no 24 pp 19618ndash19631 2015
[106] J-M Lu Q Yao and C Chen ldquoGinseng compounds an updateon their molecular mechanisms and medical applicationsrdquoCurrent Vascular Pharmacology vol 7 no 3 pp 293ndash302 2009
[107] E Hernandez-Cuellar K Tsuchiya H Hara et al ldquoCuttingedge nitric oxide inhibits the NLRP3 inflammasomerdquo TheJournal of Immunology vol 189 no 11 pp 5113ndash5117 2012
[108] B B Mishra V A K Rathinam G W Martens et alldquoNitric oxide controls the immunopathology of tuberculosis byinhibiting NLRP3 inflammasome-dependent processing of IL-1120573rdquo Nature Immunology vol 14 no 1 pp 52ndash60 2013
[109] T Matsuno S-K Jung Y Matsumoto M Saito and JMorikawa ldquoPreferential cytotoxicity to tumor cells of 35-diprenyl-4-hydroxycinnamic acid (artepillin C) isolated frompropolisrdquo Anticancer Research vol 17 no 5A pp 3565ndash35681997
16 Mediators of Inflammation
[110] X Zhang J-H Zhang X-Y Chen et al ldquoReactive oxy-gen species-induced TXNIP drives fructose-mediated hepaticinflammation and lipid accumulation through NLRP3 inflam-masome activationrdquo Antioxidants and Redox Signaling vol 22no 10 pp 848ndash870 2015
[111] A Zendedel S Johann S Mehrabi et al ldquoActivation and reg-ulation of NLRP3 inflammasome by intrathecal application ofSDF-1a in a spinal cord injury modelrdquoMolecular Neurobiologyvol 53 no 5 pp 3063ndash3075 2016
[112] H Inoue and R Nakata ldquoResveratrol targets in inflammationrdquoEndocrineMetabolic and ImmuneDisordersmdashDrug Targets vol15 no 3 pp 186ndash195 2015
[113] S S Kulkarni and C Canto ldquoThe molecular targets of resver-atrolrdquo Biochimica et Biophysica Acta (BBA)mdashMolecular Basis ofDisease vol 1852 no 6 pp 1114ndash1123 2015
[114] C A Houghton R G Fassett and J S Coombes ldquoSul-foraphane translational research from laboratory bench toclinicrdquo Nutrition Reviews vol 71 no 11 pp 709ndash726 2013
[115] A T Dinkova-Kostova W D Holtzclaw R N Cole et alldquoDirect evidence that sulfhydryl groups of Keap1 are the sensorsregulating induction of phase 2 enzymes that protect againstcarcinogens and oxidantsrdquo Proceedings of the National Academyof Sciences of the United States of America vol 99 no 18 pp11908ndash11913 2002
[116] E Heiss C Herhaus K Klimo H Bartsch and C GerhauserldquoNuclear factor 120581B is a molecular target for sulforaphane-mediated anti-inflammatory mechanismsrdquo The Journal of Bio-logical Chemistry vol 276 no 34 pp 32008ndash32015 2001
[117] A Alfieri S Srivastava R C M Siow et al ldquoSulforaphanepreconditioning of the Nrf2HO-1 defense pathway protectsthe cerebral vasculature against blood-brain barrier disruptionand neurological deficits in strokerdquo Free Radical Biology andMedicine vol 65 pp 1012ndash1022 2013
[118] C Lee G H Park S-R Lee and J-H Jang ldquoAttenuation of120573 -amyloid-induced oxidative cell death by sulforaphane viaactivation of NF-E2-related factor 2rdquo Oxidative Medicine andCellular Longevity vol 2013 Article ID 313510 12 pages 2013
[119] E Barrajon-Catalan M Herranz-Lopez J Joven et al ldquoMolec-ular promiscuity of plant polyphenols in the management ofage-related diseases far beyond their antioxidant propertiesrdquoAdvances in Experimental Medicine and Biology vol 824 pp141ndash159 2014
[120] L Bravo ldquoPolyphenols chemistry dietary sources metabolismand nutritional significancerdquo Nutrition Reviews vol 56 no 11pp 317ndash333 1998
[121] D W Lamming J G Wood and D A Sinclair ldquoSmallmolecules that regulate lifespan evidence for xenohormesisrdquoMolecular Microbiology vol 53 no 4 pp 1003ndash1009 2004
[122] K T Howitz and D A Sinclair ldquoXenohormesis sensing thechemical cues of other speciesrdquo Cell vol 133 no 3 pp 387ndash3912008
[123] P L Hooper P L Hooper M Tytell and L Vıgh ldquoXeno-hormesis health benefits from an eon of plant stress responseevolutionrdquoCell Stress and Chaperones vol 15 no 6 pp 761ndash7702010
[124] B L Queen and T O Tollefsbol ldquoPolyphenols and agingrdquoCurrent Aging Science vol 3 no 1 pp 34ndash42 2010
[125] J A Baur and D A Sinclair ldquoTherapeutic potential of resvera-trol the in vivo evidencerdquo Nature Reviews Drug Discovery vol5 no 6 pp 493ndash506 2006
[126] R A Sharma A J Gescher and W P Steward ldquoCurcumin thestory so farrdquoEuropean Journal of Cancer vol 41 no 13 pp 1955ndash1968 2005
[127] K Milton ldquoMicronutrient intakes of wild primates are humansdifferentrdquo Comparative Biochemistry and Physiology Part AMolecular amp Integrative Physiology vol 136 no 1 pp 47ndash592003
Figure 2 Chemical structure of natural compounds influencing NLRP3 inflammasome activation
potential in cancer autoimmune metabolic pulmonarycardiovascular and neurological diseases (reviewed in [98])
Brain ischemia is known to induce ER stress and inflam-matory responses leading to neuronal damage [99 100] Ina recent study glucose deprivation or hypoxia was reportedto strongly induce the production of glutamate and IL-1120573 inmouse hippocampus [53] It was shown that pretreatmentof the mouse hippocampus with curcumin reduced IL-1120573 production and this effect was attenuated by 51015840-AMP-activated protein kinase (AMPK) inhibitor suggesting thepossible involvement of AMPK The authors also foundthat curcumin attenuated glutamate-induced phosphoryla-tion of PERK and IRE1120572 the transmembrane sensors ofER stress that mediate inflammatory signals Moreoverusing a neuroblastoma cell line they showed that curcumininhibited glutamate-induced ROS generation as well asreduced glutamate-induced TXNIP expression As a possiblemolecular mechanism they found that in mice hippocam-pus glutamate stimulation increased NLRP3 expression andthe cleaved form of caspase-1 enzyme while curcuminattenuated NLRP3 and cleaved caspase-1 expression Theproduction of IL-6 a downstream target of IL-1120573 was alsoinhibited by curcumin treatment In addition curcumineffectively attenuated mitochondrial function and preventedcaspase-3 activation in hippocampus exposed to glutamate
stimulation effectively preventing glutamate-induced cellapoptosis Furthermore in rats curcumin administrationattenuated ischemic brain injury resulting from middlecerebral artery occlusion (MCAO) Based on these findingscurcumin activates AMPK that inhibits glutamate-inducedER stress and ROS production thus inhibiting TXNIP-induced NLRP3 inflammasome activation and ultimatelyreducing IL-1120573 production in mouse hippocampus limitingbrain injury
Macrophages are popular models for the study ofNLRP3 inflammasome activation In another study per-formed on mouse macrophage cell line J774A1 and peri-toneal macrophages curcumin was shown to strongly inhibitIL-1120573 secretion triggered by LPS plus nigericin aluminumATP or MSU [54] Preincubation with curcumin preventednigericin-induced intracellular potassium level decreaseattenuated lysosome damage and cathepsin B leakage andblocked high mobility group box 1 (HMGB-1) release need-less to say all of these are components that may induceNLRP3 inflammasome activation In BMDMs curcumininhibited nigericin- or aluminum crystal-induced ROS pro-duction The authors did not find obvious inhibitory effectof curcumin on JNK and p38 phosphorylation enhancedby nigericin treatment in the LPS-primed macrophageshowever they found that ERK12 phosphorylation was
6 Mediators of Inflammation
Table 1 Natural compounds effecting NLRP3 inflammasome-mediated IL-1 production
Compound Effect Mechanism Target cell Reference
Aloe vera extract Reduced IL-1120573
Reduced expression of NLRP3procaspase-1 and P2X7RInhibition of ERK p38 NF120581Bsignaling
THP-1 and human MF [51]
Aloe emodin Reduced IL-1120573 Reduced expression of NLRP3procaspase-1 and ASC expression BMDM [52]
Aloe emodin Enhanced survival NLRP3-KO mice model of septicshock [52]
Curcumin Reduced IL-1120573 andcaspase-1 inhibition Reduced ER stress through AMPK Mouse hippocampus [53]
Curcumin Reduced ROS and TXNIP expression Neuroblastoma cells [53]
Reduced expression of NLRP3 ASCand caspase-1Reduced ROS and reducedmitochondrial dysfunctionActivation of AMPK and autophagy
Murine hepatocytes [77]
dramatically downregulated In a mouse model of LPS-induced septic shock administration of curcumin signif-icantly decreased ROS level and cathepsin B leakage inperitoneal macrophages additionally peritoneal HMGB-1and IL-1120573 concentrations were downregulated resulting ina reduced LPS-induced splenomegaly These data suggestthat the observed reduction of secreted mature IL-1120573 bycurcumin is primarily attributed to the inhibition of NLRP3inflammasome activation
43 EGCG Epigallocatechin-3-gallate (EGCG) is the majorbioactive polyphenol in green tea that has a well-documentedantioxidant activity as it functions as a free-radical scavengerEGCG was reported to inhibit NF120581B activation and thesubsequent expression of several inflammatory moleculessuch as inducible nitric oxide synthase (iNOS) matrixmetalloproteinases (MMPs) IL-6 and TNF120572 Besides theanti-inflammatory role EGCG was also thought to possessantitumor effect [101]
In unilateral ureteral obstruction mice model renalinflammation has been linked to the activity of NLRP3inflammasome and the overproduction of IL-1120573 Further-more the role of NLRP3 inflammasome was proven in a vari-ety of human nondiabetic and chronic kidney diseases [102]It was reported that EGCG can prevent the development of
lupus nephritis when administered to NZBW F1 mice theclassical model of systemic lupus erythematosus [55] Thesestudies showed that EGCG treatment activated Nrf2 antiox-idant pathway induced the expression of Nrf2 downstreamenzymes like NAD(P)H dehydrogenase (quinone) 1 (NQO1)and heme oxygenase 1 (HO-1) and reduced renal oxidativestress Furthermore EGCG inhibited renal NLRP3 inflam-masome activity and the expressions of NLRP3 caspase-1and IL-1120573 were also reduced possibly due to the EGCG-induced attenuation of NF120581B pathway activity
Very recently the beneficial effect of EGCG was reportedin a contrast-inducednephropathy (CIN) ratmodel [56] CINis a common iatrogenic cause of acute kidney injury (AKI)after exposure to iodinated contrast medium characterizedby oxidative stress and inflammation [103] Similar to theprevious study they found that EGCG treatment reducedoxidative stress and increased Nrf2 and HO-1 expressionThey also found that EGCG reduced the elevated IL-1120573secretion and NLRP3 protein expression The molecularmechanisms of the observed results however were notstudied
44 Genipin Genipin is a water-soluble bifunctional cross-linking reagent that was initially isolated from the Chinesemedicinal plant Gardenia jasminoides (common name jas-mine) and it has been used for centuries as a herbal medicine
8 Mediators of Inflammation
to protect the liver and gallbladder It possesses antihyper-tensive antibleeding and antiswelling properties in additionto exhibiting anti-inflammatory characteristics Chemicallyit is an aglycone derived from an iridoid glycoside calledgeniposide that is enzymatically hydrolyzed to genipin byintestinal bacteria when administered per os [104] Genipinwas reported to inhibit mitochondrial uncoupling protein2 (UCP2) as well as superoxide-activated UCP2-mediatedproton leak occurring in a variety of diseases [105]
Recently it was shown that overexpression of UCP2caused a significant increase in NLRP3 expression in THP-1 cells and this was significantly inhibited by the adminis-tration of genipin while the levels of the adaptor proteinASC did not change [57] Interestingly genipin treatmentattenuated IL-1120573 levels in LPS-primed cells treated with ATPhowever this effect was not observed in cells treated withnigericin In addition it was also shown that inhibition ofATP-mediated inflammasome activation by genipin does notalter the production of other proinflammatory cytokines suchas IL-6 and TNF120572
In another recent study in LPS-primed murine BMDMsgenipin dramatically inhibited IL-1120573 secretion of LPS-primedcells following ATP nigericin MSU crystals or Listeriamonocytogenes treatment [58] Furthermore genipin alsoinhibited the Salmonella typhimurium-induced secretion ofIL-1120573 which is mediated via the activation of NLRC4inflammasome Similar to the previous study LPS-dependentTNF120572 secretion was not impaired by genipin Importantlygenipin treatment did not inhibit the expression of pro-IL-1120573 pro-caspase-1 or ASC proteins however it inhibitedNLRP3-dependent ASC oligomerization in addition to IL-1120573secretion and caspase-1 activation In contrast to its inhibitoryeffect on NLRP3-mediated ASC oligomerization genipindid not affect NLRC4-mediated formation of ASC speckleswhileNLRC4-mediated caspase-1 activationwas significantlydiminished These data indicate that the inhibitory effect ofgenipin on NLRC4 inflammasome activation is independentof ASC
45 Ginseng White ginseng is the naturally dried formof ginseng (Panax ginseng) while red ginseng is made bysteaming and drying fresh ginseng root Red ginseng hasbeen used for centuries as an immune-modulator and hasalso been used as an adjuvant in the treatment of infectiousand metabolic diseases Korean red ginseng contains variousactive components including saponins such as ginsenosidesand nonsaponins such as polysaccharides peptides fattyacids and mineral oils Ginsenosides are the major activecomponents of ginseng They reduce the production ofinflammatory cytokines by inhibiting NF120581B signaling [106]They also have amphiphilic nature and are able to intercalateinto the plasma membrane and influence membrane fluidityand function
It was shown that red ginseng extract (RGE) inhibitedATP- nigericin- and aluminum-induced IL-1120573 secretionin LPS-primed BMDMs and THP-1 cells and amelioratedlethality in LPS-induced septic shock model of mice [59]Furthermore RGE attenuated IL-1120573 secretion in dsDNA-transfected macrophages Similar results were obtained for
ginsenosides Furthermore it was also shown that RGE actedas an inhibitor of both NLRP3 and AIM2 inflammasomeactivations It was also demonstrated that RGE attenuated thesecretion of the active form of caspase-1 (p20)
It was previously reported that endogenousNOproducedby iNOS inhibits NLRP3 inflammasome activation via theS-nitrosylation of NLRP3 protein [107 108] A recent studyreported that ginsenosides negatively regulates LPS-inducedseptic shock in mice by a mechanism involving inhibitionof iNOS expression and the subsequent NO production[60] It was shown that ginsenosides reduced NO leveliNOS expression and ROS level in peritoneal macrophagesand BMDMs after LPS stimulation They also found thatginsenoside treatment attenuated S-nitrosylation of NLRP3protein which resulted in increased IL-beta secretion in LPS-activated macrophages
46 Mangiferin Mangiferin is a water-soluble naturalpolyphenol with a C-glycosylxanthone structure The pri-mary source of mangiferin is the mango tree (Mangiferaindica) however it is also present in some medicinal herbsin Iris unguicularis and in the honeybush a popular herbaltea from South Africa It possesses a wide spectrum ofbeneficial effects on health being used as an analgesicantidiabetic antisclerotic antimicrobial and antiviral as wellas being praised for its anti-inflammatory effects It has beenshown to regulate AMPK activity and in a recent work itwas reported that in human endothelial cells exposed tohigh glucose mangiferin reduced IL-1120573 secretion [61] Fur-thermore mangiferin attenuated IRE1 phosphorylation andreducedROS production and it decreased TXNIP expressionand inhibited ER stress Moreover a decrease in NLRP3expression and IL-1120573 production was also demonstrated
Very recently the protective role of mangiferin wasdescribed in LPS plus D-galactosamine- (D-GalN-) inducedacute liver injury [62] The authors showed that mangiferinreduced IL-1120573 secretion and ROS production and it alsoinhibited iNOS expression but induced Nrf2 and HO-1expression Furthermore it attenuated NLRP3 ASC andcaspase-1 (p10) expression and the subsequent IL-1120573 produc-tion
47 Propolis Propolis is a resinous material produced bybees (Apis mellifera L) through the mixing of secretions andenzymes from their hypopharyngeal glands with the budsof plants and wax A few hundred compounds have beendetected in raw propolis including polyphenols terpenoidssteroids sugar and amino acids Propolis composition islargely influenced by botanical origins and geographicallocation as well as by collection season One of the mostknown biological activities of propolis is related to its anti-inflammatory effect Artepillin C is a simple phenol com-posed of a single ring with two prenyl groups (35-diprenyl-4-hydroxycinnamic acid) and is the major biologically activephenolic ingredient identified in green propolis derived fromSoutheast Brazil [109]
The role of artepillin C was studied on the oxidativemetabolism of PMA-stimulated RAW2647 macrophages[63] It was shown that artepillin C significantly inhibited
Mediators of Inflammation 9
ROS release upon the NLRP3 activator nigericin treatment Itwas also suggested that artepillin C significantly contributedto the modulation of chemokine-mediated inflammation asit significantly downregulated the release of IL-1120573 IL-12p40and TNF120572 by LPS + IFN120574-treated RAW2647 cells whereasthe synthesis of IL-1120572 and IL-6 was not affected Besidesnigericin-mediated IL-1120573 production propolis also inhibitedLegionella pneumophila-induced IL-1120573 cytokine secretionin LPS-primed BMDMs This indicates that both NLRP3and NLRC4 inflammasome functions may be regulated bypropolis however further studies are required to clarify thedetailed molecular mechanism of the observed results
48 Quercetin Quercetin a kind of flavonoid found in avariety of vegetables beverages fruits and herbs exhibitsanti-inflammatory and antioxidant properties Quercetinwasreported to reduce inflammation in visceral adipose tissueprimary human adipocytes and the kidney of fructose-fedrats It was also shown to prevent diabetic kidney injury inratsHowever themechanisms of the action of quercetinwerenot clarified
It has been described that quercetin attenuated fructose-induced hyperuricemia and renal dysfunction In a studyusing streptozotocin- (STZ-) induced diabetic nephropa-thy rat model leading to hyperuricemia and dyslipidemiaquercetin was found to block NLRP3 inflammasome acti-vation [64] It was shown that the STZ-induced expres-sion of inflammasome components was restrained and IL-1120573 secretion was reduced by quercetin treatment Similarresults were obtained studying inflammatory responses infructose-induced hyperuricemia in rat [65] They showedthat fructose significantly elevated the expression of renalNLRP3 ASC and caspase-1 expression while quercetintreatment ameliorated the expression of these proteins Basedon their findings it was suggested that fructose-mediatedrenal NLRP3 inflammasome activation and proinflamma-tory cytokine overproduction may be associated with theimpaired cross talk between renal JAK2-STAT3 and PPAR-120572signaling pathway that in turn regulate renal inflammation
Furthermore it was shown that quercetin markedlyinhibited the overexpression of hepatic TXNIP in additionto reducing the production of ROS and the activation ofNLRP3 inflammasome consequently resulting in decreasedIL-1120573 secretion [66 110]They also showed that the decreasedcaspase-1 activity downregulated the caspase-1-dependentactivation of SREBPs that are involved in fatty acid andcholesterol synthesis They suggested that regulation of theTXNIP-NLRP3-SREBPs pathway by quercetin may partiallymediate the alleviation of hepatic steatosis in these diabeticrats
It was also shown that quercetin treatment regulatedAMPK pathway activation glutamine-glutamate cycle dys-function and TXNIP overexpression moreover it sup-pressed NF120581B pathway eventually leading to impairedNLRP3 inflammasome activation and IL-1120573 production inthe hypothalamus of high fructose- (HF-) fed rats [67]
Using human umbilical vein endothelial cells anothergroup reported that quercetin suppressed palmitate- (PA-) induced IL-1120573 and IL-6 induction [68] Downregulation
of NLRP3 induction was probably partially mediated viathe inhibition of ROS production and TXNIP expressionquercetin also inhibited IKK120573 activation by attenuatingits phosphorylation Furthermore quercetin treatment pro-tected cells against PA insult and significantly reduced thenumber of apoptotic cells Moreover quercetin amelioratedER stress-induced endothelial dysfunction through the acti-vation of AMPK
NLRP3 inflammasome is also recognized to have animportant role in the spinal cord tissue after traumatic spinalcord injury (SCI) and targeting the NLRP3 inflammasomecan inhibit neuroinflammation thereby improving func-tional recovery in SCI rats [111]
Very recently in a ratmodel of SCI quercetin administra-tion was shown to significantly improve functional recovery[69] Histopathological changes of the spinal cord such ascongestion edema neutrophil infiltration and structuraldisruption were inhibited by quercetin administration Toformulate a molecular mechanism the authors showed thatquercetin administration significantly reduced inflammatorycytokine IL-1120573 IL-18 and TNF120572 levels it also reduced theNLRP3 ASC and active caspase-1 protein expression andROS production However further studies are needed tobetter characterize the mechanisms of action underlying thebeneficial effects of quercetin in inflammation and immunity
49 Resveratrol Resveratrol is a polyphenol present inthe skin of grapes and mulberry commonly used in redwine production The beneficial effects of resveratrol arethought to be mediated in part by its antioxidant andanti-inflammatory properties exhibiting beneficial effectsin several diseases [112] Resveratrol exists as two isomerscis- and trans-resveratrol The cis isomer is thought to beproduced naturally during grape fermentation as a resultof isomerization of the trans isomer by yeast isomerasesFurthermore cis-resveratrol can be obtained by exposure ofthe trans isomer to sunlight Several studies have shown thattrans-resveratrol exhibits a wide range of biological activitiesincluding anti-inflammatory antioxidant anticarcinogenicantiaging antiplatelet aggregation immune-modulatory andchemoprevention effects However only few studies havebeen performed to examine the biological effects of the cisisomer Studies on cis-resveratrol have demonstrated thatit also possesses anticancer antimicrobial and antiplateletaggregation activities
One of the biological roles of resveratrol is to initiate theactivation of sirtuin 1 (Sirt1) is a deacetylase that modifies andinactivates inflammatory genes At high doses resveratrolhas been shown to activate AMPK which is involved inthe negative regulation of the NLRP3-inflammasome [113]It was also shown that ionizing radiation-induced IL-1120573secretion by human mesenchymal stem cells (MSCs) aneffect that was effectively abrogated by pretreatment withresveratrol [70] Radiation-induced increase in IL-1120573 occursvia the NLRP3 inflammasome activation however resver-atrol treatment attenuated the expression of NLRP3 It wasalso demonstrated that resveratrol treatment upregulated theexpression of Sirt1 In conclusion it is suggested that Sirt1
10 Mediators of Inflammation
inhibits NF120581B transcriptional activity through deacetylationthat in turn limits the transcription of NLRP3
In another study it was shown that cis-resveratrol pre-treatment significantly inhibited IL-1120573 secretion in THP-1 cellculture supernatants interestingly cis-resveratrol inducedIL-18 secretion under these conditions [71] Accordingly cis-resveratrol significantly reduced IL-1120573 mRNA expressionin contrast cis-resveratrol used at the same concentra-tion increased IL-18 mRNA expression Furthermore cis-resveratrol increased the mRNA and protein levels of NLRP1and NLRP3 indicating that the inhibitory effect of cis-resveratrol on IL-1120573 secretion is not due to the down-regulation of NLRP1 NLRP3 or ASC expression Similarresults were obtained on LPS-primed J774A1 macrophageswhere resveratrol inhibited the ATP-induced IL-1120573 secretionhowever in this study the authors did not find changes in theexpression of NLRP3 [72] showing that the resveratrol didnot inhibit the priming signal of NLRP3
Huang et al suggested that the inhibitory effect of cis-resveratrol on IL-1120573 secretion may be due to the reducedexpression of purinergic receptor P2X7R and the ER stressmarker GRP78 which leads to suppression of ROS pro-duction and reduced caspase-1 and caspase-4 activation Itwas found that cis-resveratrol also inhibited cyclooxygenase-(COX-) 2 expression which may be responsible for theobserved decrease of PGE2 production Furthermore inhi-bition of pro-IL-1120573 and COX-2 expression may occur bydownregulating the activation of the p38 MAPK path-way [71] Importantly in contrast to these observationsincreased phosphorylation of p38 was detected in ATP-activated J774A1 macrophages by Chang et al while itdid not significantly increase the phosphorylation levelsof ERK12 and it reduced the phosphorylation levels ofJNK12 The levels of mtDNA release into the cytosol weresignificantly reduced by resveratrol indicating that therewas less mitochondrial injury in resveratrol-treated cells[72] Furthermore the authors also showed that resveratrolincreased cellular cAMP level in J774A1 macrophages whichacts as a negative regulator of inflammatory responses andinhibits NLRP3 inflammasome activation
The effect of resveratrol on NLRP3 inflammasome wasfurther proved by a study showing that four weeks ofresveratrol administration inhibited the expression of NLRP3inflammasome components IL-1 IL-6 and TNF120572 and inlivers of HF-fed mice [73] They also showed that theregulatory effects of resveratrol on NLRP3 inflammasomemay come about through the combined effects of Sirt1 andSirt6
In a recent study [50] it was found that resveratroltreatment successfully suppressed the maturation of bothIL-1120573 and caspase-1 in response to Pam3CSK4 a TLR12agonist plus various inducers (like nigericin ATP MSUand silica) of the NLRP3-inflammasome In mouse BMDMshowever it did not affect the production of IL-1120573 medi-ated by the NLRC4-inflammasome (flagellin) or the AIM2-inflammasome (dsDNA) On a mouse model of acute goutthey indicated that resveratrol reduced the amount of matureIL-1120573 and the subsequent recruitment of neutrophils intothe peritoneal cavities of mice after challenge with MSU
crystals These findings indicate that resveratrol suppressesthe activation of the NLRP3-inflammasome both in vitroand in vivo As a possible mechanism they showed thatresveratrol at a substantially higher dosage successfullysuppressed mitochondrial ROS production Furthermoreresveratrol treatment prevented the accumulation of acety-lated 120572-tubulin thusinhibiting the proximate localization ofASC and NLRP3 in macrophages
In a very recent publication [74] the authors showed thatresveratrol preventedATP-inducedNLRP3 activation and IL-1120573 production in the BV2 cell line and in septic mice as wellThey also found that resveratrol treatment reduced NLRP3and IL-1120573 expression in the hippocampus of the mice andthey suggested that the protecting effect of resveratrol wasmediated via the increased expression of Sirt1 in BV2 cells
Another recent publication found that glucose-basedperitoneal dialysis increased mitochondrial ROS productionand subsequent IL-1120573 secretion through NLRP3 inflamma-some in human peritoneal mesothelial cells (HPMC) Asa mechanism for its action they showed that resveratrolinduced mitophagyautophagy of the cells via AMPK activa-tion and protected cells fromROS-inducedNLRP3-mediatedinflammatory injury [75]
410 Sulforaphane Sulforaphane (SFN) is a natural com-pound present in cruciferous vegetables such as broccolicabbage Brussel sprouts mustard and radish ChemicallySFN is an isothiocyanate that is known to react withsulfhydryl groups and tomodify proteins at cysteine residuesSulforaphane is produced from the precursor glucoraphaninby the enzymatic activity of myrosinase when the cell wallsof the plant are damaged for example during chewingSFN has been known as a cytoprotective agent for cancerprevention or treatment and it also has an important rolein cardiovascular neurologic and other diseases (reviewedin [114]) SFN is a known inducer of the Nrf2 antioxidantpathway as it activates the Nrf2 transcription factor byreacting with cysteine residues of its repressor Keap1 [115]In addition it also inhibits NF120581B signaling [116]
It was shown that SFN inhibited IL-1120573 processing byNLRP1- NLRP3- NLRC4- and AIM2- inflammasome com-plexes in mouse BMDMs [28] It was also demonstratedthat SFN inhibits the inflammasome in an Nrf2-independentmanner as SFN-mediated inhibition of NLRP3- andNLRC4-dependent IL-1120573 processing and secretion was not reversedin Nrf2-knockout BMDMs When SFN was added directlyto the cell lysates it did not inhibit IL-1120573 processingdemonstrating that SFN does not directly inhibit the proteaseactivity of caspase-1 The authors found that SFN-mediatedinhibition of the inflammasomes is not affected by ROSmodulation and neither proteasome-dependent proteolysisnor de novo protein synthesis is required for SFN-mediatedinhibition of the inflammasomes In a peritonitis model ofacute gout SFN treatment significantly reducedMSU crystal-induced IL-1120573 production demonstrating that SFN inhibitsthe NLRP3 inflammasome function in vivo Nonethelessthe authors concluded that SFN inhibits multiple inflam-masomes in vitro and in vivo by a mechanism independent
Mediators of Inflammation 11
ERKp38
NLRP3
ASCNLRP3
Caspase-1ROS
ER stress
P2X7R ATP
Cathepsin B
TLR
ROS
mtDNA
Sirt2
AcAc
AcAc
AMPK
A
A AC
C
C
Nrf2E
E
UCP2Ge
Ge
Ge
Gi
TXNIPC
NOGi
P
Sirt1R
R
R
R
M
M
M
Q
QQ
SS
S
R
Cardio-lipin
Acetylated 120572-tubulin
Ca2+ influx
IL-1120573
Pro-IL-1120573
K+efflux
120572-Tubulin
Pro-IL-1120573
NF120581B
Figure 3 Molecular targets of natural compounds affecting NLRP3 inflammasome-mediated IL-1 production
of inflammasome priming and Nrf2 signaling however theexact molecular mechanism was not explored
As SFN is able to penetrate the blood-brain barrier[117] it gained a considerable attention as a candidatefor Alzheimerrsquos disease (AD) therapy SFN was shown toprotect the brain from A120573-induced oxidative cell death viaactivation of Nrf2 signaling cascade [118] As A120573 fibrilshave been shown to activate NLRP3 inflammasome thequestion arose whether SFN may regulate this mechanismIn a very recent study it was shown that SFN significantlydownregulated IL-1120573 production and NLRP3 expression inA1205731ndash42 peptide-stimulated human THP-1 cells macrophages[76] It was found that A1205731ndash42 peptide-induced STAT-1phosphorylation was significantly attenuated by SFN Theauthors showed that SFN inducedNrf2 nuclear translocationwhich was subsequently accompanied by an increase in HO-1 protein levels Furthermore A1205731ndash42 peptide-induced IL-1120573 production was diminished by siRNA-mediated knock-down of Nrf2 or HO-1 They also found that the increasedproinflammatory miRNA-146a level following A1205731ndash42 treat-ment was significantly attenuated by SFN whereas miRNA-125b and miRNA-155 levels were not changed These arespecific proinflammatory miRNAs that were reported to beincreased in both the extracellular fluid and cerebrospinalfluid of AD patients In conclusion SFN can suppress A1205731ndash42-induced caspase-1-dependent inflammasome activationpossibly through inhibiting STAT-1 phosphorylation andactivation of the Nrf2HO-1 signaling pathway
Also very recently another research group reported thatoral administrations of SFN suppressed the saturated fattyacid-induced NLRP3 inflammasome activation in the liverof mice [77] They found that SFN decreased the expression
of ASC caspase-1 and IL-1120573 levels additionally it inhibitedthe activity of caspase-1 enzyme in primary hepatocytes Itwas also shown that SFN reduced the palmitate-inducedROS production by the mitochondria implying that SFNprevented mitochondrial dysfunction and this protectingmechanism was in part mediated by the activation of AMPKThey concluded that activation of AMPK and autophagy bySFN could protect from mitochondrial dysfunction inducedby saturated fatty acids resulting in a downregulation of fat-induced activation of the NLRP3 inflammasome
5 NLRP3 Inflammasome and theXenohormesis Hypothesis
As it was described in detail above polyphenols like resvera-trol curcumin EGCG and quercetin are potent inhibitors ofNLRP3 inflammasome-mediated IL-1120573 production typicallyacting at more than one element of the involved pathways(Figure 3)However it should be noted that these polyphenolshave an evenmuch broader biological effect as they influencea variety of pathways [119] though not all are directlyconnected to the function of the NLRP3 inflammasomeImportantly more than 8000 natural polyphenols have beendescribed [120] providing a large library of compounds aspotential inflammasome inhibitors Many of these polyphe-nols (such as resveratrol and curcumin) are overproducedby stressed plants triggering pathways mimicking the effectof caloric restriction It has been proposed that organismsfrom yeast to humans consuming stressed plants couldinterpret the stress signal carried by such polyphenols as apotential risk of future limitation of food availability and in
12 Mediators of Inflammation
turn adapting for the pursuit of longevity a theory termedas Xenohormesis [121ndash123] Interestingly the structurallyunrelated resveratrol and curcumin can achieve this caloricrestriction mimicking effect by activating AMPK and Sirt1[124] However polyphenols are also known to have anantioxidant effect activate glutathione S-transferases andinhibit COX enzymes among many other effects [125 126]Interestingly one of the most frequently used COX inhibitoris aspirin a derivative of another stress-induced phytochem-ical salicylic acid
A major concern of polyphenol use in therapy is thebioavailability of these compounds Nevertheless typicaldietary polyphenol intake is about 14mgkgday which iswithin the range of providing biologically active doses [127]
6 Concluding Remarks
Most of the time inflammasome-mediated IL-1120573 productionor caspase-mediated pyroptosis is beneficial for the host as itprotects from infection or prevents further damageHoweverprolonged cytokine production as in the case of sterileinflammation caused by endogenous danger signals maylead to the development of autoinflammatory or metabolicdiseases Chronic inflammation compromises the hostrsquos lifequality and requires sustained pharmacological and surgicaltreatments The paradigm of drug discovery in Westernmedicine is to develop highly selective compounds againstindividual druggable targets Currently the main treatmentmethods for these patients are targeting IL-1120573 Howeverprolonged usage of drugs may induce different side effectsfurthermore some form of medications are very expensivewhich limits their widespread use
Besides the high expenses another drawback of tradi-tional drug design is that many of the promising compoundsfail in the early or later stages of drug development Tradi-tional medicine uses many plant products to treat diseaseshowever the exact mechanisms behind their use is stillmostly lacking partially as a consequence of the pleiotropiceffect of the active compounds as detailed in this reviewNevertheless clarification of the molecular mechanism ofaction of such natural compounds already used in traditionalmedicine for quite some time will undoubtedly aid in theproduction of safe and cheap candidate medications to beused in the treatment of diseases including those appearingas a consequence of NLRP3 inflammasome-mediated IL-1120573overproduction
Competing Interests
The authors declare no conflict of interests
Acknowledgments
This work was supported by OTKA-K 109429 Szilvia Benkois a receiver of Lajos Szodoray Postdoctoral Fellowship andJanos Bolyai Postdoctoral Fellowship
References
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[5] E Gabay G Wolf Y Shavit R Yirmiya and M Tal ldquoChronicblockade of interleukin-1 (IL-1) prevents and attenuates neuro-pathic pain behavior and spontaneous ectopic neuronal activityfollowing nerve injuryrdquo European Journal of Pain vol 15 no 3pp 242ndash248 2011
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Mediators of Inflammation 13
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[32] A G Lerner J-P Upton P V K Praveen et al ldquoIRE1120572induces thioredoxin-interacting protein to activate the NLRP3inflammasome and promote programmed cell death underirremediable ER stressrdquo Cell Metabolism vol 16 no 2 pp 250ndash264 2012
[33] S Freigang F Ampenberger G Spohn et al ldquoNrf2 is essentialfor cholesterol crystal-induced inflammasome activation and
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[34] G M Tannahill and L A J OrsquoNeill ldquoThe emerging role ofmetabolic regulation in the functioning of Toll-like receptorsand the NOD-like receptor Nlrp3rdquo FEBS Letters vol 585 no11 pp 1568ndash1572 2011
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[36] F Bauernfeind E Bartok A Rieger L Franchi G Nunez andV Hornung ldquoCutting edge reactive oxygen species inhibitorsblock priming but not activation of the NLRP3 inflamma-somerdquo The Journal of Immunology vol 187 no 2 pp 613ndash6172011
[37] D Perregaux and C A Gabel ldquoInterleukin-1 beta maturationand release in response to ATP and nigericin Evidence thatpotassium depletion mediated by these agents is a necessaryand common feature of their activityrdquoThe Journal of BiologicalChemistry vol 269 no 21 pp 15195ndash15203 1994
[38] J M Kahlenberg K C Lundberg S B Kertesy Y Qu and GR Dubyak ldquoPotentiation of caspase-1 activation by the P2X7receptor is dependent on TLR signals and requires NF-120581B-driven protein synthesisrdquo Journal of Immunology vol 175 no11 pp 7611ndash7622 2005
[39] R Munoz-Planillo P Kuffa G Martınez-Colon B Smith TRajendiran and G Nunez ldquoK+ efflux is the common triggerof NLRP3 inflammasome activation by bacterial toxins andparticulate matterrdquo Immunity vol 38 no 6 pp 1142ndash1153 2013
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[41] T Murakami J Ockinger J Yu et al ldquoCritical role for calciummobilization in activation of the NLRP3 inflammasomerdquo Pro-ceedings of the National Academy of Sciences of the United Statesof America vol 109 no 28 pp 11282ndash11287 2012
[42] V Hornung F Bauernfeind A Halle et al ldquoSilica crystals andaluminum salts activate the NALP3 inflammasome throughphagosomal destabilizationrdquo Nature Immunology vol 9 no 8pp 847ndash856 2008
[43] J Dan Dunn L A J Alvarez X Zhang and T SoldatildquoReactive oxygen species and mitochondria a nexus of cellularhomeostasisrdquo Redox Biology vol 6 pp 472ndash485 2015
[44] S S Iyer Q He J R Janczy et al ldquoMitochondrial cardiolipinis required for Nlrp3 inflammasome activationrdquo Immunity vol39 no 2 pp 311ndash323 2013
[45] X Wang W Jiang Y Yan et al ldquoRNA viruses promoteactivation of the NLRP3 inflammasome through a RIP1-RIP3-DRP1 signaling pathwayrdquoNature Immunology vol 15 no 12 pp1126ndash1133 2014
[46] T Ichinohe T Yamazaki T Koshiba and Y Yanagi ldquoMitochon-drial protein mitofusin 2 is required for NLRP3 inflammasomeactivation afterRNAvirus infectionrdquoProceedings of theNationalAcademy of Sciences of the United States of America vol 110 no44 pp 17963ndash17968 2013
[47] N Subramanian K Natarajan M R Clatworthy Z Wangand R N Germain ldquoThe adaptor MAVS promotes NLRP3mitochondrial localization and inflammasome activationrdquo Cellvol 153 no 2 pp 348ndash361 2013
[48] S Y Shaw K Tran A B Castoreno et al ldquoSelective modulationof autophagy innate immunity and adaptive immunity by small
14 Mediators of Inflammation
moleculesrdquo ACS Chemical Biology vol 8 no 12 pp 2724ndash27332013
[49] K Nakahira J A Haspel V A K Rathinam et al ldquoAutophagyproteins regulate innate immune responses by inhibiting therelease of mitochondrial DNA mediated by the NALP3 inflam-masomerdquo Nature Immunology vol 12 no 3 pp 222ndash230 2011
[50] T Misawa M Takahama T Kozaki et al ldquoMicrotubule-drivenspatial arrangement ofmitochondria promotes activation of theNLRP3 inflammasomerdquo Nature Immunology vol 14 no 5 pp454ndash460 2013
[51] M M Budai A Varga S Milesz J Tozser and S BenkoldquoAloe vera downregulates LPS-induced inflammatory cytokineproduction and expression of NLRP3 inflammasome in humanmacrophagesrdquo Molecular Immunology vol 56 no 4 pp 471ndash479 2013
[52] J-W Han D-W Shim W-Y Shin et al ldquoAnti-inflammatoryeffect of emodin via attenuation of NLRP3 inflammasomeactivationrdquo International Journal of Molecular Sciences vol 16no 4 pp 8102ndash8109 2015
[53] Y Li J Li S Li et al ldquoCurcumin attenuates glutamate neurotox-icity in the hippocampus by suppression of ER stress-associatedTXNIPNLRP3 inflammasome activation in a manner depen-dent onAMPKrdquoToxicology andApplied Pharmacology vol 286no 1 pp 53ndash63 2015
[54] Z Gong J Zhou H Li et al ldquoCurcumin suppresses NLRP3inflammasome activation and protects against LPS-inducedseptic shockrdquo Molecular Nutrition and Food Research vol 59no 11 pp 2132ndash2142 2015
[55] P-Y Tsai S-M Ka J-M Chang et al ldquoEpigallocatechin-3-gallate prevents lupus nephritis development in mice viaenhancing the Nrf2 antioxidant pathway and inhibiting NLRP3inflammasome activationrdquo Free Radical Biology and Medicinevol 51 no 3 pp 744ndash754 2011
[56] Z Gao Y Han Y Hu et al ldquoTargeting HO-1 byepigallocatechin-3-gallate reduces contrast-induced renalinjury via anti-oxidative stress and anti-inflammationpathwaysrdquo PLOS ONE vol 11 no 2 article e0149032 2016
[57] V Rajanbabu L Galam J Fukumoto et al ldquoGenipin suppressesNLRP3 inflammasome activation through uncoupling protein-2rdquo Cellular Immunology vol 297 no 1 pp 40ndash45 2015
[58] S-X Yu C-T DuW Chen et al ldquoGenipin inhibits NLRP3 andNLRC4 inflammasome activation via autophagy suppressionrdquoScientific Reports vol 5 article 17935 2015
[59] J Kim H Ahn B-C Han et al ldquoKorean red ginseng extractsinhibit NLRP3 and AIM2 inflammasome activationrdquo Immunol-ogy Letters vol 158 no 1-2 pp 143ndash150 2014
[60] S-J Yoon J-Y Park S Choi et al ldquoGinsenoside Rg3 regulatesS-nitrosylation of the NLRP3 inflammasome via suppression ofiNOSrdquo Biochemical and Biophysical Research Communicationsvol 463 no 4 pp 1184ndash1189 2015
[61] J Song J Li F Hou X Wang and B Liu ldquoMangiferininhibits endoplasmic reticulum stress-associated thioredoxin-interacting proteinNLRP3 inflammasome activation with reg-ulation of AMPK in endothelial cellsrdquo Metabolism vol 64 no3 pp 428ndash437 2015
[62] C-W Pan Z-Z Pan J-J Hu et al ldquoMangiferin alleviateslipopolysaccharide and D-galactosamine-induced acute liverinjury by activating the Nrf2 pathway and inhibiting NLRP3inflammasome activationrdquo European Journal of Pharmacologyvol 770 pp 85ndash91 2016
[63] J I Hori D S Zamboni D B Carrao GHGoldman andAABerretta ldquoThe inhibition of inflammasome by Brazilian propo-lis (EPP-AF)rdquo Evidence-Based Complementary and AlternativeMedicine vol 2013 Article ID 418508 11 pages 2013
[64] C Wang Y Pan Q-Y Zhang F-M Wang and L-D KongldquoQuercetin and allopurinol ameliorate kidney injury in STZ-treated rats with regulation of renal NLRP3 inflammasomeactivation and lipid accumulationrdquo PLoS ONE vol 7 no 6Article ID e38285 2012
[65] Q-H Hu X Zhang Y Pan Y-C Li and L-D Kong ldquoAllop-urinol quercetin and rutin ameliorate renal NLRP3 inflamma-some activation and lipid accumulation in fructose-fed ratsrdquoBiochemical Pharmacology vol 84 no 1 pp 113ndash125 2012
[66] WWangCWangX-QDing et al ldquoQuercetin and allopurinolreduce liver thioredoxin-interacting protein to alleviate inflam-mation and lipid accumulation in diabetic ratsrdquo British Journalof Pharmacology vol 169 no 6 pp 1352ndash1371 2013
[67] Q-Y Zhang Y Pan R Wang et al ldquoQuercetin inhibitsAMPKTXNIP activation and reduces inflammatory lesions toimprove insulin signaling defect in the hypothalamus of highfructose-fed ratsrdquo Journal of Nutritional Biochemistry vol 25no 4 pp 420ndash428 2014
[68] J Wu X Xu Y Li et al ldquoQuercetin luteolin and epigallo-catechin gallate alleviate TXNIP and NLRP3-mediated inflam-mation and apoptosis with regulation of AMPK in endothelialcellsrdquo European Journal of Pharmacology vol 745 pp 59ndash682015
[69] W Jiang Y Huang N Han et al ldquoQuercetin suppresses NLRP3inflammasome activation and attenuates histopathology in a ratmodel of spinal cord injuryrdquo Spinal Cord vol 54 pp 592ndash5962016
[70] Y Fu Y Wang L Du et al ldquoResveratrol inhibits ionisingirradiation-induced inflammation in MSCs by activating Sirt1and limiting NLRP-3 inflammasome activationrdquo InternationalJournal ofMolecular Sciences vol 14 no 7 pp 14105ndash14118 2013
[71] T-T Huang H-C Lai Y-B Chen et al ldquoCis-Resveratrolproduces anti-inflammatory effects by inhibiting canonicaland non-canonical inflammasomes in macrophagesrdquo InnateImmunity vol 20 no 7 pp 735ndash750 2014
[72] Y-P Chang S-M Ka W-H Hsu et al ldquoResveratrol inhibitsNLRP3 inflammasome activation by preserving mitochondrialintegrity and augmenting autophagyrdquo Journal of Cellular Physi-ology vol 230 no 7 pp 1567ndash1579 2015
[73] S J Yang and Y Lim ldquoResveratrol ameliorates hepaticmetaflammation and inhibits NLRP3 inflammasome activa-tionrdquoMetabolism vol 63 no 5 pp 693ndash701 2014
[74] D-M Sui Q Xie W-J Yi et al ldquoResveratrol protects againstsepsis-associated encephalopathy and inhibits the NLRP3IL-1 120573 axis in microgliardquo Mediators of Inflammation vol 2016Article ID 1045657 10 pages 2016
[75] J Wu X Li G Zhu Y Zhang M He and J Zhang ldquoTherole of Resveratrol-inducedmitophagyautophagy in peritonealmesothelial cells inflammatory injury via NLRP3 inflamma-some activation triggered bymitochondrial ROSrdquoExperimentalCell Research vol 341 no 1 pp 42ndash53 2016
[76] Y W An K A Jhang S Y Woo J L Kang and Y HChong ldquoSulforaphane exerts its anti-inflammatory effectagainst amyloid-120573 peptide via STAT-1 dephosphorylationand activation of Nrf2HO-1 cascade in human THP-1macrophagesrdquo Neurobiology of Aging vol 38 pp 1ndash10 2016
[77] G Yang H E Lee and J Y Lee ldquoA pharmacological inhibitorof NLRP3 inflammasome prevents non-alcoholic fatty liver
Mediators of Inflammation 15
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[78] L Franchi R Munoz-Planillo and G Nunez ldquoSensing andreacting to microbes through the inflammasomesrdquo NatureImmunology vol 13 no 4 pp 325ndash332 2012
[79] S L Cassel and F S Sutterwala ldquoSterile inflammatory responsesmediated by the NLRP3 inflammasomerdquo European Journal ofImmunology vol 40 no 3 pp 607ndash611 2010
[80] M-S Tan J-T Yu T Jiang X-C Zhu and L Tan ldquoThe NLRP3inflammasome in alzheimerrsquos diseaserdquoMolecular Neurobiologyvol 48 no 3 pp 875ndash882 2013
[81] M Gold and J El Khoury ldquo120573-amyloid microglia andthe inflammasome in Alzheimerrsquos diseaserdquo Seminars inImmunopathology vol 37 no 6 pp 607ndash611 2015
[82] P M Peeters T N Perkins E F M Wouters B T Mossmanand N L Reynaert ldquoSilica induces NLRP3 inflammasomeactivation in human lung epithelial cellsrdquo Particle and FibreToxicology vol 10 no 1 article 3 2013
[83] H Watanabe O Gaide V Petrilli et al ldquoActivation of the IL-1120573-processing inflammasome is involved in contact hypersen-sitivityrdquo Journal of Investigative Dermatology vol 127 no 8 pp1956ndash1963 2007
[84] X Dai K Sayama M Tohyama et al ldquoMite allergen is adanger signal for the skin via activation of inflammasome inkeratinocytesrdquo Journal of Allergy and Clinical Immunology vol127 no 3 pp 806ndash814 2011
[85] A Varga M M Budai S Milesz A Bacsi J Tozser and SBenko ldquoRagweed pollen extract intensifies lipopolysaccharide-induced priming of NLRP3 inflammasome in humanmacrophagesrdquo Immunology vol 138 no 4 pp 392ndash4012013
[86] B Vandanmagsar Y-H Youm A Ravussin et al ldquoThe NLRP3inflammasome instigates obesity-induced inflammation andinsulin resistancerdquo Nature Medicine vol 17 no 2 pp 179ndash1892011
[87] H Wen D Gris Y Lei et al ldquoFatty acid-induced NLRP3-ASCinflammasome activation interferes with insulin signalingrdquoNature Immunology vol 12 no 5 pp 408ndash415 2011
[88] L Liang X Tan Q Zhou et al ldquoIL-1120573 triggered by pepti-doglycan and lipopolysaccharide through TLR24 and ROS-NLRP3 inflammasome- dependent pathways is involved inocular behcetrsquos diseaserdquo Investigative Ophthalmology and VisualScience vol 54 no 1 pp 402ndash414 2013
[89] S Rosengren H M Hoffman W Bugbee and D L BoyleldquoExpression and regulation of cryopyrin and related proteinsin rheumatoid arthritis synoviumrdquo Annals of the RheumaticDiseases vol 64 no 5 pp 708ndash714 2005
[90] J M Kahlenberg ldquoAnti-inflammatory panaceaThe expandingtherapeutics of interleukin-1 blockaderdquo Current Opinion inRheumatology vol 28 no 3 pp 197ndash203 2016
[91] C-H Chien M-J Lee H-C Liou H-H Liou and W-MFu ldquoLocal immunosuppressive microenvironment enhancesmigration of melanoma cells to lungs in DJ-1 knockout micerdquoPLoS ONE vol 10 no 2 Article ID e0115827 2015
[92] C Antonopoulos and G R Dubyak ldquoChemotherapy engagesmultiple pathways leading to IL-1120573 production by myeloidleukocytesrdquo OncoImmunology vol 3 no 1 Article ID e274992014
[93] E Ozaki M Campbell and S L Doyle ldquoTargeting the NLRP3inflammasome in chronic inflammatory diseases current per-spectivesrdquo Journal of Inflammation Research vol 8 pp 15ndash272015
[94] J H Hamman ldquoComposition and applications of Aloe vera leafgelrdquoMolecules vol 13 no 8 pp 1599ndash1616 2008
[95] L Langmead R J Makins and D S Rampton ldquoAnti-inflammatory effects of aloe vera gel in human colorectalmucosa in vitrordquo Alimentary Pharmacology and Therapeuticsvol 19 no 5 pp 521ndash527 2004
[96] N Yun C-H Lee and S-M Lee ldquoProtective effect of Aloe veraon polymicrobial sepsis inmicerdquo Food andChemical Toxicologyvol 47 no 6 pp 1341ndash1348 2009
[97] C S Yu F S Yu J K Chan et al ldquoAloe-emodin affects the levelsof cytokines and functions of leukocytes from Sprague-Dawleyratsrdquo In Vivo vol 20 no 4 pp 505ndash509 2006
[98] M Pulido-Moran J Moreno-Fernandez C Ramirez-Tortosaand M Ramirez-Tortosa ldquoCurcumin and healthrdquo Moleculesvol 21 no 3 article E264 2016
[99] Y-F Dong L-X Wang X Huang et al ldquoKir61 knock-down aggravates cerebral ischemiareperfusion-induced neuralinjury in micerdquo CNS Neuroscience and Therapeutics vol 19 no8 pp 617ndash624 2013
[100] P J Maier K Zemoura M A Acuna G E Yevenes HU Zeilhofer and D Benke ldquoIschemia-like oxygen and glu-cose deprivation mediates down-regulation of cell surface 120574-aminobutyric acidB receptors via the endoplasmic reticulum(ER) stress-induced transcription factor CCAATenhancer-binding protein (CEBP)-homologous protein (CHOP)rdquo TheJournal of Biological Chemistry vol 289 no 18 pp 12896ndash129072014
[101] H-Y Shin S-H Kim H-J Jeong et al ldquoEpigallocatechin-3-gallate inhibits secretion of TNF-120572 IL-6 and IL-8 through theattenuation of ERK and NF-120581B in HMC-1 cellsrdquo InternationalArchives of Allergy and Immunology vol 142 no 4 pp 335ndash3442007
[102] W P Pulskens L M Butter G J Teske et al ldquoNlrp3 preventsearly renal interstitial edema and vascular permeability inunilateral ureteral obstructionrdquo PLoS ONE vol 9 no 1 ArticleID e85775 2014
[103] S Kamath and C A Roobottom ldquoHyperdense pericardial effu-sion in dermatomyositis and contrast induced nephropathyrdquoEmergency Radiology vol 11 no 3 pp 177ndash179 2005
[104] T Akao K Kobashi and M Aburada ldquoEnzymic studies onthe animal and intestinal bacterial metabolism of geniposiderdquoBiological and Pharmaceutical Bulletin vol 17 no 12 pp 1573ndash1576 1994
[105] R Wang K C MoYung M H Zhang and K Poon ldquoUCP2-and non-UCP2-mediated electric current in eukaryotic cellsexhibits different propertiesrdquo Environmental Science and Pollu-tion Research vol 22 no 24 pp 19618ndash19631 2015
[106] J-M Lu Q Yao and C Chen ldquoGinseng compounds an updateon their molecular mechanisms and medical applicationsrdquoCurrent Vascular Pharmacology vol 7 no 3 pp 293ndash302 2009
[107] E Hernandez-Cuellar K Tsuchiya H Hara et al ldquoCuttingedge nitric oxide inhibits the NLRP3 inflammasomerdquo TheJournal of Immunology vol 189 no 11 pp 5113ndash5117 2012
[108] B B Mishra V A K Rathinam G W Martens et alldquoNitric oxide controls the immunopathology of tuberculosis byinhibiting NLRP3 inflammasome-dependent processing of IL-1120573rdquo Nature Immunology vol 14 no 1 pp 52ndash60 2013
[109] T Matsuno S-K Jung Y Matsumoto M Saito and JMorikawa ldquoPreferential cytotoxicity to tumor cells of 35-diprenyl-4-hydroxycinnamic acid (artepillin C) isolated frompropolisrdquo Anticancer Research vol 17 no 5A pp 3565ndash35681997
16 Mediators of Inflammation
[110] X Zhang J-H Zhang X-Y Chen et al ldquoReactive oxy-gen species-induced TXNIP drives fructose-mediated hepaticinflammation and lipid accumulation through NLRP3 inflam-masome activationrdquo Antioxidants and Redox Signaling vol 22no 10 pp 848ndash870 2015
[111] A Zendedel S Johann S Mehrabi et al ldquoActivation and reg-ulation of NLRP3 inflammasome by intrathecal application ofSDF-1a in a spinal cord injury modelrdquoMolecular Neurobiologyvol 53 no 5 pp 3063ndash3075 2016
[112] H Inoue and R Nakata ldquoResveratrol targets in inflammationrdquoEndocrineMetabolic and ImmuneDisordersmdashDrug Targets vol15 no 3 pp 186ndash195 2015
[113] S S Kulkarni and C Canto ldquoThe molecular targets of resver-atrolrdquo Biochimica et Biophysica Acta (BBA)mdashMolecular Basis ofDisease vol 1852 no 6 pp 1114ndash1123 2015
[114] C A Houghton R G Fassett and J S Coombes ldquoSul-foraphane translational research from laboratory bench toclinicrdquo Nutrition Reviews vol 71 no 11 pp 709ndash726 2013
[115] A T Dinkova-Kostova W D Holtzclaw R N Cole et alldquoDirect evidence that sulfhydryl groups of Keap1 are the sensorsregulating induction of phase 2 enzymes that protect againstcarcinogens and oxidantsrdquo Proceedings of the National Academyof Sciences of the United States of America vol 99 no 18 pp11908ndash11913 2002
[116] E Heiss C Herhaus K Klimo H Bartsch and C GerhauserldquoNuclear factor 120581B is a molecular target for sulforaphane-mediated anti-inflammatory mechanismsrdquo The Journal of Bio-logical Chemistry vol 276 no 34 pp 32008ndash32015 2001
[117] A Alfieri S Srivastava R C M Siow et al ldquoSulforaphanepreconditioning of the Nrf2HO-1 defense pathway protectsthe cerebral vasculature against blood-brain barrier disruptionand neurological deficits in strokerdquo Free Radical Biology andMedicine vol 65 pp 1012ndash1022 2013
[118] C Lee G H Park S-R Lee and J-H Jang ldquoAttenuation of120573 -amyloid-induced oxidative cell death by sulforaphane viaactivation of NF-E2-related factor 2rdquo Oxidative Medicine andCellular Longevity vol 2013 Article ID 313510 12 pages 2013
[119] E Barrajon-Catalan M Herranz-Lopez J Joven et al ldquoMolec-ular promiscuity of plant polyphenols in the management ofage-related diseases far beyond their antioxidant propertiesrdquoAdvances in Experimental Medicine and Biology vol 824 pp141ndash159 2014
[120] L Bravo ldquoPolyphenols chemistry dietary sources metabolismand nutritional significancerdquo Nutrition Reviews vol 56 no 11pp 317ndash333 1998
[121] D W Lamming J G Wood and D A Sinclair ldquoSmallmolecules that regulate lifespan evidence for xenohormesisrdquoMolecular Microbiology vol 53 no 4 pp 1003ndash1009 2004
[122] K T Howitz and D A Sinclair ldquoXenohormesis sensing thechemical cues of other speciesrdquo Cell vol 133 no 3 pp 387ndash3912008
[123] P L Hooper P L Hooper M Tytell and L Vıgh ldquoXeno-hormesis health benefits from an eon of plant stress responseevolutionrdquoCell Stress and Chaperones vol 15 no 6 pp 761ndash7702010
[124] B L Queen and T O Tollefsbol ldquoPolyphenols and agingrdquoCurrent Aging Science vol 3 no 1 pp 34ndash42 2010
[125] J A Baur and D A Sinclair ldquoTherapeutic potential of resvera-trol the in vivo evidencerdquo Nature Reviews Drug Discovery vol5 no 6 pp 493ndash506 2006
[126] R A Sharma A J Gescher and W P Steward ldquoCurcumin thestory so farrdquoEuropean Journal of Cancer vol 41 no 13 pp 1955ndash1968 2005
[127] K Milton ldquoMicronutrient intakes of wild primates are humansdifferentrdquo Comparative Biochemistry and Physiology Part AMolecular amp Integrative Physiology vol 136 no 1 pp 47ndash592003
Reduced expression of NLRP3 ASCand caspase-1Reduced ROS and reducedmitochondrial dysfunctionActivation of AMPK and autophagy
Murine hepatocytes [77]
dramatically downregulated In a mouse model of LPS-induced septic shock administration of curcumin signif-icantly decreased ROS level and cathepsin B leakage inperitoneal macrophages additionally peritoneal HMGB-1and IL-1120573 concentrations were downregulated resulting ina reduced LPS-induced splenomegaly These data suggestthat the observed reduction of secreted mature IL-1120573 bycurcumin is primarily attributed to the inhibition of NLRP3inflammasome activation
43 EGCG Epigallocatechin-3-gallate (EGCG) is the majorbioactive polyphenol in green tea that has a well-documentedantioxidant activity as it functions as a free-radical scavengerEGCG was reported to inhibit NF120581B activation and thesubsequent expression of several inflammatory moleculessuch as inducible nitric oxide synthase (iNOS) matrixmetalloproteinases (MMPs) IL-6 and TNF120572 Besides theanti-inflammatory role EGCG was also thought to possessantitumor effect [101]
In unilateral ureteral obstruction mice model renalinflammation has been linked to the activity of NLRP3inflammasome and the overproduction of IL-1120573 Further-more the role of NLRP3 inflammasome was proven in a vari-ety of human nondiabetic and chronic kidney diseases [102]It was reported that EGCG can prevent the development of
lupus nephritis when administered to NZBW F1 mice theclassical model of systemic lupus erythematosus [55] Thesestudies showed that EGCG treatment activated Nrf2 antiox-idant pathway induced the expression of Nrf2 downstreamenzymes like NAD(P)H dehydrogenase (quinone) 1 (NQO1)and heme oxygenase 1 (HO-1) and reduced renal oxidativestress Furthermore EGCG inhibited renal NLRP3 inflam-masome activity and the expressions of NLRP3 caspase-1and IL-1120573 were also reduced possibly due to the EGCG-induced attenuation of NF120581B pathway activity
Very recently the beneficial effect of EGCG was reportedin a contrast-inducednephropathy (CIN) ratmodel [56] CINis a common iatrogenic cause of acute kidney injury (AKI)after exposure to iodinated contrast medium characterizedby oxidative stress and inflammation [103] Similar to theprevious study they found that EGCG treatment reducedoxidative stress and increased Nrf2 and HO-1 expressionThey also found that EGCG reduced the elevated IL-1120573secretion and NLRP3 protein expression The molecularmechanisms of the observed results however were notstudied
44 Genipin Genipin is a water-soluble bifunctional cross-linking reagent that was initially isolated from the Chinesemedicinal plant Gardenia jasminoides (common name jas-mine) and it has been used for centuries as a herbal medicine
8 Mediators of Inflammation
to protect the liver and gallbladder It possesses antihyper-tensive antibleeding and antiswelling properties in additionto exhibiting anti-inflammatory characteristics Chemicallyit is an aglycone derived from an iridoid glycoside calledgeniposide that is enzymatically hydrolyzed to genipin byintestinal bacteria when administered per os [104] Genipinwas reported to inhibit mitochondrial uncoupling protein2 (UCP2) as well as superoxide-activated UCP2-mediatedproton leak occurring in a variety of diseases [105]
Recently it was shown that overexpression of UCP2caused a significant increase in NLRP3 expression in THP-1 cells and this was significantly inhibited by the adminis-tration of genipin while the levels of the adaptor proteinASC did not change [57] Interestingly genipin treatmentattenuated IL-1120573 levels in LPS-primed cells treated with ATPhowever this effect was not observed in cells treated withnigericin In addition it was also shown that inhibition ofATP-mediated inflammasome activation by genipin does notalter the production of other proinflammatory cytokines suchas IL-6 and TNF120572
In another recent study in LPS-primed murine BMDMsgenipin dramatically inhibited IL-1120573 secretion of LPS-primedcells following ATP nigericin MSU crystals or Listeriamonocytogenes treatment [58] Furthermore genipin alsoinhibited the Salmonella typhimurium-induced secretion ofIL-1120573 which is mediated via the activation of NLRC4inflammasome Similar to the previous study LPS-dependentTNF120572 secretion was not impaired by genipin Importantlygenipin treatment did not inhibit the expression of pro-IL-1120573 pro-caspase-1 or ASC proteins however it inhibitedNLRP3-dependent ASC oligomerization in addition to IL-1120573secretion and caspase-1 activation In contrast to its inhibitoryeffect on NLRP3-mediated ASC oligomerization genipindid not affect NLRC4-mediated formation of ASC speckleswhileNLRC4-mediated caspase-1 activationwas significantlydiminished These data indicate that the inhibitory effect ofgenipin on NLRC4 inflammasome activation is independentof ASC
45 Ginseng White ginseng is the naturally dried formof ginseng (Panax ginseng) while red ginseng is made bysteaming and drying fresh ginseng root Red ginseng hasbeen used for centuries as an immune-modulator and hasalso been used as an adjuvant in the treatment of infectiousand metabolic diseases Korean red ginseng contains variousactive components including saponins such as ginsenosidesand nonsaponins such as polysaccharides peptides fattyacids and mineral oils Ginsenosides are the major activecomponents of ginseng They reduce the production ofinflammatory cytokines by inhibiting NF120581B signaling [106]They also have amphiphilic nature and are able to intercalateinto the plasma membrane and influence membrane fluidityand function
It was shown that red ginseng extract (RGE) inhibitedATP- nigericin- and aluminum-induced IL-1120573 secretionin LPS-primed BMDMs and THP-1 cells and amelioratedlethality in LPS-induced septic shock model of mice [59]Furthermore RGE attenuated IL-1120573 secretion in dsDNA-transfected macrophages Similar results were obtained for
ginsenosides Furthermore it was also shown that RGE actedas an inhibitor of both NLRP3 and AIM2 inflammasomeactivations It was also demonstrated that RGE attenuated thesecretion of the active form of caspase-1 (p20)
It was previously reported that endogenousNOproducedby iNOS inhibits NLRP3 inflammasome activation via theS-nitrosylation of NLRP3 protein [107 108] A recent studyreported that ginsenosides negatively regulates LPS-inducedseptic shock in mice by a mechanism involving inhibitionof iNOS expression and the subsequent NO production[60] It was shown that ginsenosides reduced NO leveliNOS expression and ROS level in peritoneal macrophagesand BMDMs after LPS stimulation They also found thatginsenoside treatment attenuated S-nitrosylation of NLRP3protein which resulted in increased IL-beta secretion in LPS-activated macrophages
46 Mangiferin Mangiferin is a water-soluble naturalpolyphenol with a C-glycosylxanthone structure The pri-mary source of mangiferin is the mango tree (Mangiferaindica) however it is also present in some medicinal herbsin Iris unguicularis and in the honeybush a popular herbaltea from South Africa It possesses a wide spectrum ofbeneficial effects on health being used as an analgesicantidiabetic antisclerotic antimicrobial and antiviral as wellas being praised for its anti-inflammatory effects It has beenshown to regulate AMPK activity and in a recent work itwas reported that in human endothelial cells exposed tohigh glucose mangiferin reduced IL-1120573 secretion [61] Fur-thermore mangiferin attenuated IRE1 phosphorylation andreducedROS production and it decreased TXNIP expressionand inhibited ER stress Moreover a decrease in NLRP3expression and IL-1120573 production was also demonstrated
Very recently the protective role of mangiferin wasdescribed in LPS plus D-galactosamine- (D-GalN-) inducedacute liver injury [62] The authors showed that mangiferinreduced IL-1120573 secretion and ROS production and it alsoinhibited iNOS expression but induced Nrf2 and HO-1expression Furthermore it attenuated NLRP3 ASC andcaspase-1 (p10) expression and the subsequent IL-1120573 produc-tion
47 Propolis Propolis is a resinous material produced bybees (Apis mellifera L) through the mixing of secretions andenzymes from their hypopharyngeal glands with the budsof plants and wax A few hundred compounds have beendetected in raw propolis including polyphenols terpenoidssteroids sugar and amino acids Propolis composition islargely influenced by botanical origins and geographicallocation as well as by collection season One of the mostknown biological activities of propolis is related to its anti-inflammatory effect Artepillin C is a simple phenol com-posed of a single ring with two prenyl groups (35-diprenyl-4-hydroxycinnamic acid) and is the major biologically activephenolic ingredient identified in green propolis derived fromSoutheast Brazil [109]
The role of artepillin C was studied on the oxidativemetabolism of PMA-stimulated RAW2647 macrophages[63] It was shown that artepillin C significantly inhibited
Mediators of Inflammation 9
ROS release upon the NLRP3 activator nigericin treatment Itwas also suggested that artepillin C significantly contributedto the modulation of chemokine-mediated inflammation asit significantly downregulated the release of IL-1120573 IL-12p40and TNF120572 by LPS + IFN120574-treated RAW2647 cells whereasthe synthesis of IL-1120572 and IL-6 was not affected Besidesnigericin-mediated IL-1120573 production propolis also inhibitedLegionella pneumophila-induced IL-1120573 cytokine secretionin LPS-primed BMDMs This indicates that both NLRP3and NLRC4 inflammasome functions may be regulated bypropolis however further studies are required to clarify thedetailed molecular mechanism of the observed results
48 Quercetin Quercetin a kind of flavonoid found in avariety of vegetables beverages fruits and herbs exhibitsanti-inflammatory and antioxidant properties Quercetinwasreported to reduce inflammation in visceral adipose tissueprimary human adipocytes and the kidney of fructose-fedrats It was also shown to prevent diabetic kidney injury inratsHowever themechanisms of the action of quercetinwerenot clarified
It has been described that quercetin attenuated fructose-induced hyperuricemia and renal dysfunction In a studyusing streptozotocin- (STZ-) induced diabetic nephropa-thy rat model leading to hyperuricemia and dyslipidemiaquercetin was found to block NLRP3 inflammasome acti-vation [64] It was shown that the STZ-induced expres-sion of inflammasome components was restrained and IL-1120573 secretion was reduced by quercetin treatment Similarresults were obtained studying inflammatory responses infructose-induced hyperuricemia in rat [65] They showedthat fructose significantly elevated the expression of renalNLRP3 ASC and caspase-1 expression while quercetintreatment ameliorated the expression of these proteins Basedon their findings it was suggested that fructose-mediatedrenal NLRP3 inflammasome activation and proinflamma-tory cytokine overproduction may be associated with theimpaired cross talk between renal JAK2-STAT3 and PPAR-120572signaling pathway that in turn regulate renal inflammation
Furthermore it was shown that quercetin markedlyinhibited the overexpression of hepatic TXNIP in additionto reducing the production of ROS and the activation ofNLRP3 inflammasome consequently resulting in decreasedIL-1120573 secretion [66 110]They also showed that the decreasedcaspase-1 activity downregulated the caspase-1-dependentactivation of SREBPs that are involved in fatty acid andcholesterol synthesis They suggested that regulation of theTXNIP-NLRP3-SREBPs pathway by quercetin may partiallymediate the alleviation of hepatic steatosis in these diabeticrats
It was also shown that quercetin treatment regulatedAMPK pathway activation glutamine-glutamate cycle dys-function and TXNIP overexpression moreover it sup-pressed NF120581B pathway eventually leading to impairedNLRP3 inflammasome activation and IL-1120573 production inthe hypothalamus of high fructose- (HF-) fed rats [67]
Using human umbilical vein endothelial cells anothergroup reported that quercetin suppressed palmitate- (PA-) induced IL-1120573 and IL-6 induction [68] Downregulation
of NLRP3 induction was probably partially mediated viathe inhibition of ROS production and TXNIP expressionquercetin also inhibited IKK120573 activation by attenuatingits phosphorylation Furthermore quercetin treatment pro-tected cells against PA insult and significantly reduced thenumber of apoptotic cells Moreover quercetin amelioratedER stress-induced endothelial dysfunction through the acti-vation of AMPK
NLRP3 inflammasome is also recognized to have animportant role in the spinal cord tissue after traumatic spinalcord injury (SCI) and targeting the NLRP3 inflammasomecan inhibit neuroinflammation thereby improving func-tional recovery in SCI rats [111]
Very recently in a ratmodel of SCI quercetin administra-tion was shown to significantly improve functional recovery[69] Histopathological changes of the spinal cord such ascongestion edema neutrophil infiltration and structuraldisruption were inhibited by quercetin administration Toformulate a molecular mechanism the authors showed thatquercetin administration significantly reduced inflammatorycytokine IL-1120573 IL-18 and TNF120572 levels it also reduced theNLRP3 ASC and active caspase-1 protein expression andROS production However further studies are needed tobetter characterize the mechanisms of action underlying thebeneficial effects of quercetin in inflammation and immunity
49 Resveratrol Resveratrol is a polyphenol present inthe skin of grapes and mulberry commonly used in redwine production The beneficial effects of resveratrol arethought to be mediated in part by its antioxidant andanti-inflammatory properties exhibiting beneficial effectsin several diseases [112] Resveratrol exists as two isomerscis- and trans-resveratrol The cis isomer is thought to beproduced naturally during grape fermentation as a resultof isomerization of the trans isomer by yeast isomerasesFurthermore cis-resveratrol can be obtained by exposure ofthe trans isomer to sunlight Several studies have shown thattrans-resveratrol exhibits a wide range of biological activitiesincluding anti-inflammatory antioxidant anticarcinogenicantiaging antiplatelet aggregation immune-modulatory andchemoprevention effects However only few studies havebeen performed to examine the biological effects of the cisisomer Studies on cis-resveratrol have demonstrated thatit also possesses anticancer antimicrobial and antiplateletaggregation activities
One of the biological roles of resveratrol is to initiate theactivation of sirtuin 1 (Sirt1) is a deacetylase that modifies andinactivates inflammatory genes At high doses resveratrolhas been shown to activate AMPK which is involved inthe negative regulation of the NLRP3-inflammasome [113]It was also shown that ionizing radiation-induced IL-1120573secretion by human mesenchymal stem cells (MSCs) aneffect that was effectively abrogated by pretreatment withresveratrol [70] Radiation-induced increase in IL-1120573 occursvia the NLRP3 inflammasome activation however resver-atrol treatment attenuated the expression of NLRP3 It wasalso demonstrated that resveratrol treatment upregulated theexpression of Sirt1 In conclusion it is suggested that Sirt1
10 Mediators of Inflammation
inhibits NF120581B transcriptional activity through deacetylationthat in turn limits the transcription of NLRP3
In another study it was shown that cis-resveratrol pre-treatment significantly inhibited IL-1120573 secretion in THP-1 cellculture supernatants interestingly cis-resveratrol inducedIL-18 secretion under these conditions [71] Accordingly cis-resveratrol significantly reduced IL-1120573 mRNA expressionin contrast cis-resveratrol used at the same concentra-tion increased IL-18 mRNA expression Furthermore cis-resveratrol increased the mRNA and protein levels of NLRP1and NLRP3 indicating that the inhibitory effect of cis-resveratrol on IL-1120573 secretion is not due to the down-regulation of NLRP1 NLRP3 or ASC expression Similarresults were obtained on LPS-primed J774A1 macrophageswhere resveratrol inhibited the ATP-induced IL-1120573 secretionhowever in this study the authors did not find changes in theexpression of NLRP3 [72] showing that the resveratrol didnot inhibit the priming signal of NLRP3
Huang et al suggested that the inhibitory effect of cis-resveratrol on IL-1120573 secretion may be due to the reducedexpression of purinergic receptor P2X7R and the ER stressmarker GRP78 which leads to suppression of ROS pro-duction and reduced caspase-1 and caspase-4 activation Itwas found that cis-resveratrol also inhibited cyclooxygenase-(COX-) 2 expression which may be responsible for theobserved decrease of PGE2 production Furthermore inhi-bition of pro-IL-1120573 and COX-2 expression may occur bydownregulating the activation of the p38 MAPK path-way [71] Importantly in contrast to these observationsincreased phosphorylation of p38 was detected in ATP-activated J774A1 macrophages by Chang et al while itdid not significantly increase the phosphorylation levelsof ERK12 and it reduced the phosphorylation levels ofJNK12 The levels of mtDNA release into the cytosol weresignificantly reduced by resveratrol indicating that therewas less mitochondrial injury in resveratrol-treated cells[72] Furthermore the authors also showed that resveratrolincreased cellular cAMP level in J774A1 macrophages whichacts as a negative regulator of inflammatory responses andinhibits NLRP3 inflammasome activation
The effect of resveratrol on NLRP3 inflammasome wasfurther proved by a study showing that four weeks ofresveratrol administration inhibited the expression of NLRP3inflammasome components IL-1 IL-6 and TNF120572 and inlivers of HF-fed mice [73] They also showed that theregulatory effects of resveratrol on NLRP3 inflammasomemay come about through the combined effects of Sirt1 andSirt6
In a recent study [50] it was found that resveratroltreatment successfully suppressed the maturation of bothIL-1120573 and caspase-1 in response to Pam3CSK4 a TLR12agonist plus various inducers (like nigericin ATP MSUand silica) of the NLRP3-inflammasome In mouse BMDMshowever it did not affect the production of IL-1120573 medi-ated by the NLRC4-inflammasome (flagellin) or the AIM2-inflammasome (dsDNA) On a mouse model of acute goutthey indicated that resveratrol reduced the amount of matureIL-1120573 and the subsequent recruitment of neutrophils intothe peritoneal cavities of mice after challenge with MSU
crystals These findings indicate that resveratrol suppressesthe activation of the NLRP3-inflammasome both in vitroand in vivo As a possible mechanism they showed thatresveratrol at a substantially higher dosage successfullysuppressed mitochondrial ROS production Furthermoreresveratrol treatment prevented the accumulation of acety-lated 120572-tubulin thusinhibiting the proximate localization ofASC and NLRP3 in macrophages
In a very recent publication [74] the authors showed thatresveratrol preventedATP-inducedNLRP3 activation and IL-1120573 production in the BV2 cell line and in septic mice as wellThey also found that resveratrol treatment reduced NLRP3and IL-1120573 expression in the hippocampus of the mice andthey suggested that the protecting effect of resveratrol wasmediated via the increased expression of Sirt1 in BV2 cells
Another recent publication found that glucose-basedperitoneal dialysis increased mitochondrial ROS productionand subsequent IL-1120573 secretion through NLRP3 inflamma-some in human peritoneal mesothelial cells (HPMC) Asa mechanism for its action they showed that resveratrolinduced mitophagyautophagy of the cells via AMPK activa-tion and protected cells fromROS-inducedNLRP3-mediatedinflammatory injury [75]
410 Sulforaphane Sulforaphane (SFN) is a natural com-pound present in cruciferous vegetables such as broccolicabbage Brussel sprouts mustard and radish ChemicallySFN is an isothiocyanate that is known to react withsulfhydryl groups and tomodify proteins at cysteine residuesSulforaphane is produced from the precursor glucoraphaninby the enzymatic activity of myrosinase when the cell wallsof the plant are damaged for example during chewingSFN has been known as a cytoprotective agent for cancerprevention or treatment and it also has an important rolein cardiovascular neurologic and other diseases (reviewedin [114]) SFN is a known inducer of the Nrf2 antioxidantpathway as it activates the Nrf2 transcription factor byreacting with cysteine residues of its repressor Keap1 [115]In addition it also inhibits NF120581B signaling [116]
It was shown that SFN inhibited IL-1120573 processing byNLRP1- NLRP3- NLRC4- and AIM2- inflammasome com-plexes in mouse BMDMs [28] It was also demonstratedthat SFN inhibits the inflammasome in an Nrf2-independentmanner as SFN-mediated inhibition of NLRP3- andNLRC4-dependent IL-1120573 processing and secretion was not reversedin Nrf2-knockout BMDMs When SFN was added directlyto the cell lysates it did not inhibit IL-1120573 processingdemonstrating that SFN does not directly inhibit the proteaseactivity of caspase-1 The authors found that SFN-mediatedinhibition of the inflammasomes is not affected by ROSmodulation and neither proteasome-dependent proteolysisnor de novo protein synthesis is required for SFN-mediatedinhibition of the inflammasomes In a peritonitis model ofacute gout SFN treatment significantly reducedMSU crystal-induced IL-1120573 production demonstrating that SFN inhibitsthe NLRP3 inflammasome function in vivo Nonethelessthe authors concluded that SFN inhibits multiple inflam-masomes in vitro and in vivo by a mechanism independent
Mediators of Inflammation 11
ERKp38
NLRP3
ASCNLRP3
Caspase-1ROS
ER stress
P2X7R ATP
Cathepsin B
TLR
ROS
mtDNA
Sirt2
AcAc
AcAc
AMPK
A
A AC
C
C
Nrf2E
E
UCP2Ge
Ge
Ge
Gi
TXNIPC
NOGi
P
Sirt1R
R
R
R
M
M
M
Q
QQ
SS
S
R
Cardio-lipin
Acetylated 120572-tubulin
Ca2+ influx
IL-1120573
Pro-IL-1120573
K+efflux
120572-Tubulin
Pro-IL-1120573
NF120581B
Figure 3 Molecular targets of natural compounds affecting NLRP3 inflammasome-mediated IL-1 production
of inflammasome priming and Nrf2 signaling however theexact molecular mechanism was not explored
As SFN is able to penetrate the blood-brain barrier[117] it gained a considerable attention as a candidatefor Alzheimerrsquos disease (AD) therapy SFN was shown toprotect the brain from A120573-induced oxidative cell death viaactivation of Nrf2 signaling cascade [118] As A120573 fibrilshave been shown to activate NLRP3 inflammasome thequestion arose whether SFN may regulate this mechanismIn a very recent study it was shown that SFN significantlydownregulated IL-1120573 production and NLRP3 expression inA1205731ndash42 peptide-stimulated human THP-1 cells macrophages[76] It was found that A1205731ndash42 peptide-induced STAT-1phosphorylation was significantly attenuated by SFN Theauthors showed that SFN inducedNrf2 nuclear translocationwhich was subsequently accompanied by an increase in HO-1 protein levels Furthermore A1205731ndash42 peptide-induced IL-1120573 production was diminished by siRNA-mediated knock-down of Nrf2 or HO-1 They also found that the increasedproinflammatory miRNA-146a level following A1205731ndash42 treat-ment was significantly attenuated by SFN whereas miRNA-125b and miRNA-155 levels were not changed These arespecific proinflammatory miRNAs that were reported to beincreased in both the extracellular fluid and cerebrospinalfluid of AD patients In conclusion SFN can suppress A1205731ndash42-induced caspase-1-dependent inflammasome activationpossibly through inhibiting STAT-1 phosphorylation andactivation of the Nrf2HO-1 signaling pathway
Also very recently another research group reported thatoral administrations of SFN suppressed the saturated fattyacid-induced NLRP3 inflammasome activation in the liverof mice [77] They found that SFN decreased the expression
of ASC caspase-1 and IL-1120573 levels additionally it inhibitedthe activity of caspase-1 enzyme in primary hepatocytes Itwas also shown that SFN reduced the palmitate-inducedROS production by the mitochondria implying that SFNprevented mitochondrial dysfunction and this protectingmechanism was in part mediated by the activation of AMPKThey concluded that activation of AMPK and autophagy bySFN could protect from mitochondrial dysfunction inducedby saturated fatty acids resulting in a downregulation of fat-induced activation of the NLRP3 inflammasome
5 NLRP3 Inflammasome and theXenohormesis Hypothesis
As it was described in detail above polyphenols like resvera-trol curcumin EGCG and quercetin are potent inhibitors ofNLRP3 inflammasome-mediated IL-1120573 production typicallyacting at more than one element of the involved pathways(Figure 3)However it should be noted that these polyphenolshave an evenmuch broader biological effect as they influencea variety of pathways [119] though not all are directlyconnected to the function of the NLRP3 inflammasomeImportantly more than 8000 natural polyphenols have beendescribed [120] providing a large library of compounds aspotential inflammasome inhibitors Many of these polyphe-nols (such as resveratrol and curcumin) are overproducedby stressed plants triggering pathways mimicking the effectof caloric restriction It has been proposed that organismsfrom yeast to humans consuming stressed plants couldinterpret the stress signal carried by such polyphenols as apotential risk of future limitation of food availability and in
12 Mediators of Inflammation
turn adapting for the pursuit of longevity a theory termedas Xenohormesis [121ndash123] Interestingly the structurallyunrelated resveratrol and curcumin can achieve this caloricrestriction mimicking effect by activating AMPK and Sirt1[124] However polyphenols are also known to have anantioxidant effect activate glutathione S-transferases andinhibit COX enzymes among many other effects [125 126]Interestingly one of the most frequently used COX inhibitoris aspirin a derivative of another stress-induced phytochem-ical salicylic acid
A major concern of polyphenol use in therapy is thebioavailability of these compounds Nevertheless typicaldietary polyphenol intake is about 14mgkgday which iswithin the range of providing biologically active doses [127]
6 Concluding Remarks
Most of the time inflammasome-mediated IL-1120573 productionor caspase-mediated pyroptosis is beneficial for the host as itprotects from infection or prevents further damageHoweverprolonged cytokine production as in the case of sterileinflammation caused by endogenous danger signals maylead to the development of autoinflammatory or metabolicdiseases Chronic inflammation compromises the hostrsquos lifequality and requires sustained pharmacological and surgicaltreatments The paradigm of drug discovery in Westernmedicine is to develop highly selective compounds againstindividual druggable targets Currently the main treatmentmethods for these patients are targeting IL-1120573 Howeverprolonged usage of drugs may induce different side effectsfurthermore some form of medications are very expensivewhich limits their widespread use
Besides the high expenses another drawback of tradi-tional drug design is that many of the promising compoundsfail in the early or later stages of drug development Tradi-tional medicine uses many plant products to treat diseaseshowever the exact mechanisms behind their use is stillmostly lacking partially as a consequence of the pleiotropiceffect of the active compounds as detailed in this reviewNevertheless clarification of the molecular mechanism ofaction of such natural compounds already used in traditionalmedicine for quite some time will undoubtedly aid in theproduction of safe and cheap candidate medications to beused in the treatment of diseases including those appearingas a consequence of NLRP3 inflammasome-mediated IL-1120573overproduction
Competing Interests
The authors declare no conflict of interests
Acknowledgments
This work was supported by OTKA-K 109429 Szilvia Benkois a receiver of Lajos Szodoray Postdoctoral Fellowship andJanos Bolyai Postdoctoral Fellowship
References
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[2] G Meng F Zhang I Fuss A Kitani and W Strober ldquoA muta-tion in the Nlrp3 gene causing inflammasome hyperactivationpotentiates Th17 cell-dominant immune responsesrdquo Immunityvol 30 no 6 pp 860ndash874 2009
[3] D Lasiglie E Traggiai S Federici et al ldquoRole of IL-1 beta in thedevelopment of human TH17 cells lesson fromNLPR3mutatedpatientsrdquo PLoS ONE vol 6 no 5 Article ID e20014 2011
[4] H Schneider F Pitossi D Balschun A Wagner A Del Reyand H O Besedovsky ldquoA neuromodulatory role of interleukin-1120573 in the hippocampusrdquo Proceedings of the National Academy ofSciences of the United States of America vol 95 no 13 pp 7778ndash7783 1998
[5] E Gabay G Wolf Y Shavit R Yirmiya and M Tal ldquoChronicblockade of interleukin-1 (IL-1) prevents and attenuates neuro-pathic pain behavior and spontaneous ectopic neuronal activityfollowing nerve injuryrdquo European Journal of Pain vol 15 no 3pp 242ndash248 2011
[6] A del Rey A V Apkarian M Martina and H O BesedovskyldquoChronic neuropathic pain-like behavior and brain-borne IL-1120573rdquo Annals of the New York Academy of Sciences vol 1262 no 1pp 101ndash107 2012
[7] R Yirmiya and I Goshen ldquoImmune modulation of learningmemory neural plasticity and neurogenesisrdquo Brain Behaviorand Immunity vol 25 no 2 pp 181ndash213 2011
[8] M R de Zoete N W Palm S Zhu and R A FlavellldquoInflammasomesrdquo Cold Spring Harbor Perspectives in Biologyvol 6 no 12 Article ID a016287 2014
[9] M Dagenais A Skeldon and M Saleh ldquoThe inflammasomein memory of Dr Jurg Tschopprdquo Cell Death and Differentiationvol 19 no 1 pp 5ndash12 2012
[10] T-D Kanneganti N OzorenM Body-Malapel et al ldquoBacterialRNA and small antiviral compounds activate caspase-1 throughcryopyrinNalp3rdquoNature vol 440 no 7081 pp 233ndash236 2006
[11] S Mariathasan D S Weiss K Newton et al ldquoCryopyrinactivates the inflammasome in response to toxins and ATPrdquoNature vol 440 no 7081 pp 228ndash232 2006
[12] A G Hise J Tomalka S Ganesan et al ldquoAn essential role forthe NLRP3 inflammasome in host defense against the humanfungal pathogen candida albicansrdquo Cell Host and Microbe vol5 no 5 pp 487ndash497 2009
[13] M T Shio S C Eisenbarth M Savaria et al ldquoMalarialhemozoin activates theNLRP3 inflammasome through Lyn andSyk kinasesrdquo PLoS Pathogens vol 5 no 8 article e10005592009
[14] F Martinon V Petrilli A Mayor A Tardivel and J TschoppldquoGout-associated uric acid crystals activate the NALP3 inflam-masomerdquo Nature vol 440 no 7081 pp 237ndash241 2006
[15] J Tschopp and K Schroder ldquoNLRP3 inflammasome activationthe convergence of multiple signalling pathways on ROS pro-ductionrdquo Nature Reviews Immunology vol 10 no 3 pp 210ndash215 2010
[16] C Dostert V Petrilli R Van Bruggen C Steele B TMossmanand J Tschopp ldquoInnate immune activation through Nalp3inflammasome sensing of asbestos and silicardquo Science vol 320no 5876 pp 674ndash677 2008
Mediators of Inflammation 13
[17] A Halle V Hornung G C Petzold et al ldquoThe NALP3inflammasome is involved in the innate immune response toamyloid-120573rdquoNature Immunology vol 9 no 8 pp 857ndash865 2008
[18] B Pazar H-K Ea S Narayan et al ldquoBasic calcium phosphatecrystals induce monocytemacrophage IL-1120573 secretion throughthe NLRP3 inflammasome in vitrordquo Journal of Immunology vol186 no 4 pp 2495ndash2502 2011
[19] P Duewell H Kono K J Rayner et al ldquoNLRP3 inflammasomesare required for atherogenesis and activated by cholesterolcrystalsrdquo Nature vol 464 no 7293 pp 1357ndash1361 2010
[20] S Benko D J Philpott and S E Girardin ldquoThe microbial anddanger signals that activate Nod-like receptorsrdquo Cytokine vol43 no 3 pp 368ndash373 2008
[21] F G Bauernfeind G Horvath A Stutz et al ldquoCutting edgeNF-120581B activating pattern recognition and cytokine receptorslicense NLRP3 inflammasome activation by regulating NLRP3expressionrdquo Journal of Immunology vol 183 no 2 pp 787ndash7912009
[22] M G Ghonime O R Shamaa S Das et al ldquoInflammasomepriming by lipopolysaccharide is dependent upon ERK signal-ing and proteasome functionrdquo Journal of Immunology vol 192no 8 pp 3881ndash3888 2014
[23] Q He H You X-M Li T-H Liu P Wang and B-E WangldquoHMGB1 promotes the synthesis of pro-il-1120573 and pro-il-18by activation of p38 MAPK and NF-kB through receptorsfor advanced glycation end-products in macrophagesrdquo AsianPacific Journal of Cancer Prevention vol 13 no 4 pp 1365ndash13702012
[24] C Jin and R A Flavell ldquoMolecular mechanism of NLRP3inflammasome activationrdquo Journal of Clinical Immunology vol30 no 5 pp 628ndash631 2010
[25] S MMan and T-D Kanneganti ldquoRegulation of inflammasomeactivationrdquo Immunological Reviews vol 265 no 1 pp 6ndash212015
[26] K Shimada T R Crother J Karlin et al ldquoOxidized mito-chondrial DNA activates the NLRP3 inflammasome duringapoptosisrdquo Immunity vol 36 no 3 pp 401ndash414 2012
[27] G-S Lee N Subramanian A I Kim et al ldquoThe calcium-sensing receptor regulates the NLRP3 inflammasome throughCa2+ and cAMPrdquo Nature vol 491 no 7427 pp 123ndash127 2012
[28] A J Greaney SH Leppla andMMoayeri ldquoBacterial exotoxinsand the inflammasomerdquo Frontiers in Immunology vol 6 article570 2015
[29] E I Elliott and F S Sutterwala ldquoInitiation and perpetuation ofNLRP3 inflammasome activation and assemblyrdquo ImmunologicalReviews vol 265 no 1 pp 35ndash52 2015
[30] A Sokolovska C E Becker W K E Ip et al ldquoActiva-tion of caspase-1 by the NLRP3 inflammasome regulates theNADPHoxidaseNOX2 to control phagosome functionrdquoNatureImmunology vol 14 no 6 pp 543ndash553 2013
[31] S Kim Y Joe S O Jeong et al ldquoEndoplasmic reticulum stressis sufficient for the induction of IL-1120573 production via activationof the NF-120581B and inflammasome pathwaysrdquo Innate Immunityvol 20 no 8 pp 799ndash815 2014
[32] A G Lerner J-P Upton P V K Praveen et al ldquoIRE1120572induces thioredoxin-interacting protein to activate the NLRP3inflammasome and promote programmed cell death underirremediable ER stressrdquo Cell Metabolism vol 16 no 2 pp 250ndash264 2012
[33] S Freigang F Ampenberger G Spohn et al ldquoNrf2 is essentialfor cholesterol crystal-induced inflammasome activation and
exacerbation of atherosclerosisrdquo European Journal of Immunol-ogy vol 41 no 7 pp 2040ndash2051 2011
[34] G M Tannahill and L A J OrsquoNeill ldquoThe emerging role ofmetabolic regulation in the functioning of Toll-like receptorsand the NOD-like receptor Nlrp3rdquo FEBS Letters vol 585 no11 pp 1568ndash1572 2011
[35] M Haneklaus and L A J OrsquoNeill ldquoNLRP3 at the interfaceof metabolism and inflammationrdquo Immunological Reviews vol265 no 1 pp 53ndash62 2015
[36] F Bauernfeind E Bartok A Rieger L Franchi G Nunez andV Hornung ldquoCutting edge reactive oxygen species inhibitorsblock priming but not activation of the NLRP3 inflamma-somerdquo The Journal of Immunology vol 187 no 2 pp 613ndash6172011
[37] D Perregaux and C A Gabel ldquoInterleukin-1 beta maturationand release in response to ATP and nigericin Evidence thatpotassium depletion mediated by these agents is a necessaryand common feature of their activityrdquoThe Journal of BiologicalChemistry vol 269 no 21 pp 15195ndash15203 1994
[38] J M Kahlenberg K C Lundberg S B Kertesy Y Qu and GR Dubyak ldquoPotentiation of caspase-1 activation by the P2X7receptor is dependent on TLR signals and requires NF-120581B-driven protein synthesisrdquo Journal of Immunology vol 175 no11 pp 7611ndash7622 2005
[39] R Munoz-Planillo P Kuffa G Martınez-Colon B Smith TRajendiran and G Nunez ldquoK+ efflux is the common triggerof NLRP3 inflammasome activation by bacterial toxins andparticulate matterrdquo Immunity vol 38 no 6 pp 1142ndash1153 2013
[40] V Petrilli S Papin C Dostert A Mayor F Martinon and JTschopp ldquoActivation of the NALP3 inflammasome is triggeredby low intracellular potassium concentrationrdquo Cell Death andDifferentiation vol 14 no 9 pp 1583ndash1589 2007
[41] T Murakami J Ockinger J Yu et al ldquoCritical role for calciummobilization in activation of the NLRP3 inflammasomerdquo Pro-ceedings of the National Academy of Sciences of the United Statesof America vol 109 no 28 pp 11282ndash11287 2012
[42] V Hornung F Bauernfeind A Halle et al ldquoSilica crystals andaluminum salts activate the NALP3 inflammasome throughphagosomal destabilizationrdquo Nature Immunology vol 9 no 8pp 847ndash856 2008
[43] J Dan Dunn L A J Alvarez X Zhang and T SoldatildquoReactive oxygen species and mitochondria a nexus of cellularhomeostasisrdquo Redox Biology vol 6 pp 472ndash485 2015
[44] S S Iyer Q He J R Janczy et al ldquoMitochondrial cardiolipinis required for Nlrp3 inflammasome activationrdquo Immunity vol39 no 2 pp 311ndash323 2013
[45] X Wang W Jiang Y Yan et al ldquoRNA viruses promoteactivation of the NLRP3 inflammasome through a RIP1-RIP3-DRP1 signaling pathwayrdquoNature Immunology vol 15 no 12 pp1126ndash1133 2014
[46] T Ichinohe T Yamazaki T Koshiba and Y Yanagi ldquoMitochon-drial protein mitofusin 2 is required for NLRP3 inflammasomeactivation afterRNAvirus infectionrdquoProceedings of theNationalAcademy of Sciences of the United States of America vol 110 no44 pp 17963ndash17968 2013
[47] N Subramanian K Natarajan M R Clatworthy Z Wangand R N Germain ldquoThe adaptor MAVS promotes NLRP3mitochondrial localization and inflammasome activationrdquo Cellvol 153 no 2 pp 348ndash361 2013
[48] S Y Shaw K Tran A B Castoreno et al ldquoSelective modulationof autophagy innate immunity and adaptive immunity by small
14 Mediators of Inflammation
moleculesrdquo ACS Chemical Biology vol 8 no 12 pp 2724ndash27332013
[49] K Nakahira J A Haspel V A K Rathinam et al ldquoAutophagyproteins regulate innate immune responses by inhibiting therelease of mitochondrial DNA mediated by the NALP3 inflam-masomerdquo Nature Immunology vol 12 no 3 pp 222ndash230 2011
[50] T Misawa M Takahama T Kozaki et al ldquoMicrotubule-drivenspatial arrangement ofmitochondria promotes activation of theNLRP3 inflammasomerdquo Nature Immunology vol 14 no 5 pp454ndash460 2013
[51] M M Budai A Varga S Milesz J Tozser and S BenkoldquoAloe vera downregulates LPS-induced inflammatory cytokineproduction and expression of NLRP3 inflammasome in humanmacrophagesrdquo Molecular Immunology vol 56 no 4 pp 471ndash479 2013
[52] J-W Han D-W Shim W-Y Shin et al ldquoAnti-inflammatoryeffect of emodin via attenuation of NLRP3 inflammasomeactivationrdquo International Journal of Molecular Sciences vol 16no 4 pp 8102ndash8109 2015
[53] Y Li J Li S Li et al ldquoCurcumin attenuates glutamate neurotox-icity in the hippocampus by suppression of ER stress-associatedTXNIPNLRP3 inflammasome activation in a manner depen-dent onAMPKrdquoToxicology andApplied Pharmacology vol 286no 1 pp 53ndash63 2015
[54] Z Gong J Zhou H Li et al ldquoCurcumin suppresses NLRP3inflammasome activation and protects against LPS-inducedseptic shockrdquo Molecular Nutrition and Food Research vol 59no 11 pp 2132ndash2142 2015
[55] P-Y Tsai S-M Ka J-M Chang et al ldquoEpigallocatechin-3-gallate prevents lupus nephritis development in mice viaenhancing the Nrf2 antioxidant pathway and inhibiting NLRP3inflammasome activationrdquo Free Radical Biology and Medicinevol 51 no 3 pp 744ndash754 2011
[56] Z Gao Y Han Y Hu et al ldquoTargeting HO-1 byepigallocatechin-3-gallate reduces contrast-induced renalinjury via anti-oxidative stress and anti-inflammationpathwaysrdquo PLOS ONE vol 11 no 2 article e0149032 2016
[57] V Rajanbabu L Galam J Fukumoto et al ldquoGenipin suppressesNLRP3 inflammasome activation through uncoupling protein-2rdquo Cellular Immunology vol 297 no 1 pp 40ndash45 2015
[58] S-X Yu C-T DuW Chen et al ldquoGenipin inhibits NLRP3 andNLRC4 inflammasome activation via autophagy suppressionrdquoScientific Reports vol 5 article 17935 2015
[59] J Kim H Ahn B-C Han et al ldquoKorean red ginseng extractsinhibit NLRP3 and AIM2 inflammasome activationrdquo Immunol-ogy Letters vol 158 no 1-2 pp 143ndash150 2014
[60] S-J Yoon J-Y Park S Choi et al ldquoGinsenoside Rg3 regulatesS-nitrosylation of the NLRP3 inflammasome via suppression ofiNOSrdquo Biochemical and Biophysical Research Communicationsvol 463 no 4 pp 1184ndash1189 2015
[61] J Song J Li F Hou X Wang and B Liu ldquoMangiferininhibits endoplasmic reticulum stress-associated thioredoxin-interacting proteinNLRP3 inflammasome activation with reg-ulation of AMPK in endothelial cellsrdquo Metabolism vol 64 no3 pp 428ndash437 2015
[62] C-W Pan Z-Z Pan J-J Hu et al ldquoMangiferin alleviateslipopolysaccharide and D-galactosamine-induced acute liverinjury by activating the Nrf2 pathway and inhibiting NLRP3inflammasome activationrdquo European Journal of Pharmacologyvol 770 pp 85ndash91 2016
[63] J I Hori D S Zamboni D B Carrao GHGoldman andAABerretta ldquoThe inhibition of inflammasome by Brazilian propo-lis (EPP-AF)rdquo Evidence-Based Complementary and AlternativeMedicine vol 2013 Article ID 418508 11 pages 2013
[64] C Wang Y Pan Q-Y Zhang F-M Wang and L-D KongldquoQuercetin and allopurinol ameliorate kidney injury in STZ-treated rats with regulation of renal NLRP3 inflammasomeactivation and lipid accumulationrdquo PLoS ONE vol 7 no 6Article ID e38285 2012
[65] Q-H Hu X Zhang Y Pan Y-C Li and L-D Kong ldquoAllop-urinol quercetin and rutin ameliorate renal NLRP3 inflamma-some activation and lipid accumulation in fructose-fed ratsrdquoBiochemical Pharmacology vol 84 no 1 pp 113ndash125 2012
[66] WWangCWangX-QDing et al ldquoQuercetin and allopurinolreduce liver thioredoxin-interacting protein to alleviate inflam-mation and lipid accumulation in diabetic ratsrdquo British Journalof Pharmacology vol 169 no 6 pp 1352ndash1371 2013
[67] Q-Y Zhang Y Pan R Wang et al ldquoQuercetin inhibitsAMPKTXNIP activation and reduces inflammatory lesions toimprove insulin signaling defect in the hypothalamus of highfructose-fed ratsrdquo Journal of Nutritional Biochemistry vol 25no 4 pp 420ndash428 2014
[68] J Wu X Xu Y Li et al ldquoQuercetin luteolin and epigallo-catechin gallate alleviate TXNIP and NLRP3-mediated inflam-mation and apoptosis with regulation of AMPK in endothelialcellsrdquo European Journal of Pharmacology vol 745 pp 59ndash682015
[69] W Jiang Y Huang N Han et al ldquoQuercetin suppresses NLRP3inflammasome activation and attenuates histopathology in a ratmodel of spinal cord injuryrdquo Spinal Cord vol 54 pp 592ndash5962016
[70] Y Fu Y Wang L Du et al ldquoResveratrol inhibits ionisingirradiation-induced inflammation in MSCs by activating Sirt1and limiting NLRP-3 inflammasome activationrdquo InternationalJournal ofMolecular Sciences vol 14 no 7 pp 14105ndash14118 2013
[71] T-T Huang H-C Lai Y-B Chen et al ldquoCis-Resveratrolproduces anti-inflammatory effects by inhibiting canonicaland non-canonical inflammasomes in macrophagesrdquo InnateImmunity vol 20 no 7 pp 735ndash750 2014
[72] Y-P Chang S-M Ka W-H Hsu et al ldquoResveratrol inhibitsNLRP3 inflammasome activation by preserving mitochondrialintegrity and augmenting autophagyrdquo Journal of Cellular Physi-ology vol 230 no 7 pp 1567ndash1579 2015
[73] S J Yang and Y Lim ldquoResveratrol ameliorates hepaticmetaflammation and inhibits NLRP3 inflammasome activa-tionrdquoMetabolism vol 63 no 5 pp 693ndash701 2014
[74] D-M Sui Q Xie W-J Yi et al ldquoResveratrol protects againstsepsis-associated encephalopathy and inhibits the NLRP3IL-1 120573 axis in microgliardquo Mediators of Inflammation vol 2016Article ID 1045657 10 pages 2016
[75] J Wu X Li G Zhu Y Zhang M He and J Zhang ldquoTherole of Resveratrol-inducedmitophagyautophagy in peritonealmesothelial cells inflammatory injury via NLRP3 inflamma-some activation triggered bymitochondrial ROSrdquoExperimentalCell Research vol 341 no 1 pp 42ndash53 2016
[76] Y W An K A Jhang S Y Woo J L Kang and Y HChong ldquoSulforaphane exerts its anti-inflammatory effectagainst amyloid-120573 peptide via STAT-1 dephosphorylationand activation of Nrf2HO-1 cascade in human THP-1macrophagesrdquo Neurobiology of Aging vol 38 pp 1ndash10 2016
[77] G Yang H E Lee and J Y Lee ldquoA pharmacological inhibitorof NLRP3 inflammasome prevents non-alcoholic fatty liver
Mediators of Inflammation 15
disease in a mouse model induced by high fat dietrdquo ScientificReports vol 6 Article ID 24399 2016
[78] L Franchi R Munoz-Planillo and G Nunez ldquoSensing andreacting to microbes through the inflammasomesrdquo NatureImmunology vol 13 no 4 pp 325ndash332 2012
[79] S L Cassel and F S Sutterwala ldquoSterile inflammatory responsesmediated by the NLRP3 inflammasomerdquo European Journal ofImmunology vol 40 no 3 pp 607ndash611 2010
[80] M-S Tan J-T Yu T Jiang X-C Zhu and L Tan ldquoThe NLRP3inflammasome in alzheimerrsquos diseaserdquoMolecular Neurobiologyvol 48 no 3 pp 875ndash882 2013
[81] M Gold and J El Khoury ldquo120573-amyloid microglia andthe inflammasome in Alzheimerrsquos diseaserdquo Seminars inImmunopathology vol 37 no 6 pp 607ndash611 2015
[82] P M Peeters T N Perkins E F M Wouters B T Mossmanand N L Reynaert ldquoSilica induces NLRP3 inflammasomeactivation in human lung epithelial cellsrdquo Particle and FibreToxicology vol 10 no 1 article 3 2013
[83] H Watanabe O Gaide V Petrilli et al ldquoActivation of the IL-1120573-processing inflammasome is involved in contact hypersen-sitivityrdquo Journal of Investigative Dermatology vol 127 no 8 pp1956ndash1963 2007
[84] X Dai K Sayama M Tohyama et al ldquoMite allergen is adanger signal for the skin via activation of inflammasome inkeratinocytesrdquo Journal of Allergy and Clinical Immunology vol127 no 3 pp 806ndash814 2011
[85] A Varga M M Budai S Milesz A Bacsi J Tozser and SBenko ldquoRagweed pollen extract intensifies lipopolysaccharide-induced priming of NLRP3 inflammasome in humanmacrophagesrdquo Immunology vol 138 no 4 pp 392ndash4012013
[86] B Vandanmagsar Y-H Youm A Ravussin et al ldquoThe NLRP3inflammasome instigates obesity-induced inflammation andinsulin resistancerdquo Nature Medicine vol 17 no 2 pp 179ndash1892011
[87] H Wen D Gris Y Lei et al ldquoFatty acid-induced NLRP3-ASCinflammasome activation interferes with insulin signalingrdquoNature Immunology vol 12 no 5 pp 408ndash415 2011
[88] L Liang X Tan Q Zhou et al ldquoIL-1120573 triggered by pepti-doglycan and lipopolysaccharide through TLR24 and ROS-NLRP3 inflammasome- dependent pathways is involved inocular behcetrsquos diseaserdquo Investigative Ophthalmology and VisualScience vol 54 no 1 pp 402ndash414 2013
[89] S Rosengren H M Hoffman W Bugbee and D L BoyleldquoExpression and regulation of cryopyrin and related proteinsin rheumatoid arthritis synoviumrdquo Annals of the RheumaticDiseases vol 64 no 5 pp 708ndash714 2005
[90] J M Kahlenberg ldquoAnti-inflammatory panaceaThe expandingtherapeutics of interleukin-1 blockaderdquo Current Opinion inRheumatology vol 28 no 3 pp 197ndash203 2016
[91] C-H Chien M-J Lee H-C Liou H-H Liou and W-MFu ldquoLocal immunosuppressive microenvironment enhancesmigration of melanoma cells to lungs in DJ-1 knockout micerdquoPLoS ONE vol 10 no 2 Article ID e0115827 2015
[92] C Antonopoulos and G R Dubyak ldquoChemotherapy engagesmultiple pathways leading to IL-1120573 production by myeloidleukocytesrdquo OncoImmunology vol 3 no 1 Article ID e274992014
[93] E Ozaki M Campbell and S L Doyle ldquoTargeting the NLRP3inflammasome in chronic inflammatory diseases current per-spectivesrdquo Journal of Inflammation Research vol 8 pp 15ndash272015
[94] J H Hamman ldquoComposition and applications of Aloe vera leafgelrdquoMolecules vol 13 no 8 pp 1599ndash1616 2008
[95] L Langmead R J Makins and D S Rampton ldquoAnti-inflammatory effects of aloe vera gel in human colorectalmucosa in vitrordquo Alimentary Pharmacology and Therapeuticsvol 19 no 5 pp 521ndash527 2004
[96] N Yun C-H Lee and S-M Lee ldquoProtective effect of Aloe veraon polymicrobial sepsis inmicerdquo Food andChemical Toxicologyvol 47 no 6 pp 1341ndash1348 2009
[97] C S Yu F S Yu J K Chan et al ldquoAloe-emodin affects the levelsof cytokines and functions of leukocytes from Sprague-Dawleyratsrdquo In Vivo vol 20 no 4 pp 505ndash509 2006
[98] M Pulido-Moran J Moreno-Fernandez C Ramirez-Tortosaand M Ramirez-Tortosa ldquoCurcumin and healthrdquo Moleculesvol 21 no 3 article E264 2016
[99] Y-F Dong L-X Wang X Huang et al ldquoKir61 knock-down aggravates cerebral ischemiareperfusion-induced neuralinjury in micerdquo CNS Neuroscience and Therapeutics vol 19 no8 pp 617ndash624 2013
[100] P J Maier K Zemoura M A Acuna G E Yevenes HU Zeilhofer and D Benke ldquoIschemia-like oxygen and glu-cose deprivation mediates down-regulation of cell surface 120574-aminobutyric acidB receptors via the endoplasmic reticulum(ER) stress-induced transcription factor CCAATenhancer-binding protein (CEBP)-homologous protein (CHOP)rdquo TheJournal of Biological Chemistry vol 289 no 18 pp 12896ndash129072014
[101] H-Y Shin S-H Kim H-J Jeong et al ldquoEpigallocatechin-3-gallate inhibits secretion of TNF-120572 IL-6 and IL-8 through theattenuation of ERK and NF-120581B in HMC-1 cellsrdquo InternationalArchives of Allergy and Immunology vol 142 no 4 pp 335ndash3442007
[102] W P Pulskens L M Butter G J Teske et al ldquoNlrp3 preventsearly renal interstitial edema and vascular permeability inunilateral ureteral obstructionrdquo PLoS ONE vol 9 no 1 ArticleID e85775 2014
[103] S Kamath and C A Roobottom ldquoHyperdense pericardial effu-sion in dermatomyositis and contrast induced nephropathyrdquoEmergency Radiology vol 11 no 3 pp 177ndash179 2005
[104] T Akao K Kobashi and M Aburada ldquoEnzymic studies onthe animal and intestinal bacterial metabolism of geniposiderdquoBiological and Pharmaceutical Bulletin vol 17 no 12 pp 1573ndash1576 1994
[105] R Wang K C MoYung M H Zhang and K Poon ldquoUCP2-and non-UCP2-mediated electric current in eukaryotic cellsexhibits different propertiesrdquo Environmental Science and Pollu-tion Research vol 22 no 24 pp 19618ndash19631 2015
[106] J-M Lu Q Yao and C Chen ldquoGinseng compounds an updateon their molecular mechanisms and medical applicationsrdquoCurrent Vascular Pharmacology vol 7 no 3 pp 293ndash302 2009
[107] E Hernandez-Cuellar K Tsuchiya H Hara et al ldquoCuttingedge nitric oxide inhibits the NLRP3 inflammasomerdquo TheJournal of Immunology vol 189 no 11 pp 5113ndash5117 2012
[108] B B Mishra V A K Rathinam G W Martens et alldquoNitric oxide controls the immunopathology of tuberculosis byinhibiting NLRP3 inflammasome-dependent processing of IL-1120573rdquo Nature Immunology vol 14 no 1 pp 52ndash60 2013
[109] T Matsuno S-K Jung Y Matsumoto M Saito and JMorikawa ldquoPreferential cytotoxicity to tumor cells of 35-diprenyl-4-hydroxycinnamic acid (artepillin C) isolated frompropolisrdquo Anticancer Research vol 17 no 5A pp 3565ndash35681997
16 Mediators of Inflammation
[110] X Zhang J-H Zhang X-Y Chen et al ldquoReactive oxy-gen species-induced TXNIP drives fructose-mediated hepaticinflammation and lipid accumulation through NLRP3 inflam-masome activationrdquo Antioxidants and Redox Signaling vol 22no 10 pp 848ndash870 2015
[111] A Zendedel S Johann S Mehrabi et al ldquoActivation and reg-ulation of NLRP3 inflammasome by intrathecal application ofSDF-1a in a spinal cord injury modelrdquoMolecular Neurobiologyvol 53 no 5 pp 3063ndash3075 2016
[112] H Inoue and R Nakata ldquoResveratrol targets in inflammationrdquoEndocrineMetabolic and ImmuneDisordersmdashDrug Targets vol15 no 3 pp 186ndash195 2015
[113] S S Kulkarni and C Canto ldquoThe molecular targets of resver-atrolrdquo Biochimica et Biophysica Acta (BBA)mdashMolecular Basis ofDisease vol 1852 no 6 pp 1114ndash1123 2015
[114] C A Houghton R G Fassett and J S Coombes ldquoSul-foraphane translational research from laboratory bench toclinicrdquo Nutrition Reviews vol 71 no 11 pp 709ndash726 2013
[115] A T Dinkova-Kostova W D Holtzclaw R N Cole et alldquoDirect evidence that sulfhydryl groups of Keap1 are the sensorsregulating induction of phase 2 enzymes that protect againstcarcinogens and oxidantsrdquo Proceedings of the National Academyof Sciences of the United States of America vol 99 no 18 pp11908ndash11913 2002
[116] E Heiss C Herhaus K Klimo H Bartsch and C GerhauserldquoNuclear factor 120581B is a molecular target for sulforaphane-mediated anti-inflammatory mechanismsrdquo The Journal of Bio-logical Chemistry vol 276 no 34 pp 32008ndash32015 2001
[117] A Alfieri S Srivastava R C M Siow et al ldquoSulforaphanepreconditioning of the Nrf2HO-1 defense pathway protectsthe cerebral vasculature against blood-brain barrier disruptionand neurological deficits in strokerdquo Free Radical Biology andMedicine vol 65 pp 1012ndash1022 2013
[118] C Lee G H Park S-R Lee and J-H Jang ldquoAttenuation of120573 -amyloid-induced oxidative cell death by sulforaphane viaactivation of NF-E2-related factor 2rdquo Oxidative Medicine andCellular Longevity vol 2013 Article ID 313510 12 pages 2013
[119] E Barrajon-Catalan M Herranz-Lopez J Joven et al ldquoMolec-ular promiscuity of plant polyphenols in the management ofage-related diseases far beyond their antioxidant propertiesrdquoAdvances in Experimental Medicine and Biology vol 824 pp141ndash159 2014
[120] L Bravo ldquoPolyphenols chemistry dietary sources metabolismand nutritional significancerdquo Nutrition Reviews vol 56 no 11pp 317ndash333 1998
[121] D W Lamming J G Wood and D A Sinclair ldquoSmallmolecules that regulate lifespan evidence for xenohormesisrdquoMolecular Microbiology vol 53 no 4 pp 1003ndash1009 2004
[122] K T Howitz and D A Sinclair ldquoXenohormesis sensing thechemical cues of other speciesrdquo Cell vol 133 no 3 pp 387ndash3912008
[123] P L Hooper P L Hooper M Tytell and L Vıgh ldquoXeno-hormesis health benefits from an eon of plant stress responseevolutionrdquoCell Stress and Chaperones vol 15 no 6 pp 761ndash7702010
[124] B L Queen and T O Tollefsbol ldquoPolyphenols and agingrdquoCurrent Aging Science vol 3 no 1 pp 34ndash42 2010
[125] J A Baur and D A Sinclair ldquoTherapeutic potential of resvera-trol the in vivo evidencerdquo Nature Reviews Drug Discovery vol5 no 6 pp 493ndash506 2006
[126] R A Sharma A J Gescher and W P Steward ldquoCurcumin thestory so farrdquoEuropean Journal of Cancer vol 41 no 13 pp 1955ndash1968 2005
[127] K Milton ldquoMicronutrient intakes of wild primates are humansdifferentrdquo Comparative Biochemistry and Physiology Part AMolecular amp Integrative Physiology vol 136 no 1 pp 47ndash592003
Reduced expression of NLRP3 ASCand caspase-1Reduced ROS and reducedmitochondrial dysfunctionActivation of AMPK and autophagy
Murine hepatocytes [77]
dramatically downregulated In a mouse model of LPS-induced septic shock administration of curcumin signif-icantly decreased ROS level and cathepsin B leakage inperitoneal macrophages additionally peritoneal HMGB-1and IL-1120573 concentrations were downregulated resulting ina reduced LPS-induced splenomegaly These data suggestthat the observed reduction of secreted mature IL-1120573 bycurcumin is primarily attributed to the inhibition of NLRP3inflammasome activation
43 EGCG Epigallocatechin-3-gallate (EGCG) is the majorbioactive polyphenol in green tea that has a well-documentedantioxidant activity as it functions as a free-radical scavengerEGCG was reported to inhibit NF120581B activation and thesubsequent expression of several inflammatory moleculessuch as inducible nitric oxide synthase (iNOS) matrixmetalloproteinases (MMPs) IL-6 and TNF120572 Besides theanti-inflammatory role EGCG was also thought to possessantitumor effect [101]
In unilateral ureteral obstruction mice model renalinflammation has been linked to the activity of NLRP3inflammasome and the overproduction of IL-1120573 Further-more the role of NLRP3 inflammasome was proven in a vari-ety of human nondiabetic and chronic kidney diseases [102]It was reported that EGCG can prevent the development of
lupus nephritis when administered to NZBW F1 mice theclassical model of systemic lupus erythematosus [55] Thesestudies showed that EGCG treatment activated Nrf2 antiox-idant pathway induced the expression of Nrf2 downstreamenzymes like NAD(P)H dehydrogenase (quinone) 1 (NQO1)and heme oxygenase 1 (HO-1) and reduced renal oxidativestress Furthermore EGCG inhibited renal NLRP3 inflam-masome activity and the expressions of NLRP3 caspase-1and IL-1120573 were also reduced possibly due to the EGCG-induced attenuation of NF120581B pathway activity
Very recently the beneficial effect of EGCG was reportedin a contrast-inducednephropathy (CIN) ratmodel [56] CINis a common iatrogenic cause of acute kidney injury (AKI)after exposure to iodinated contrast medium characterizedby oxidative stress and inflammation [103] Similar to theprevious study they found that EGCG treatment reducedoxidative stress and increased Nrf2 and HO-1 expressionThey also found that EGCG reduced the elevated IL-1120573secretion and NLRP3 protein expression The molecularmechanisms of the observed results however were notstudied
44 Genipin Genipin is a water-soluble bifunctional cross-linking reagent that was initially isolated from the Chinesemedicinal plant Gardenia jasminoides (common name jas-mine) and it has been used for centuries as a herbal medicine
8 Mediators of Inflammation
to protect the liver and gallbladder It possesses antihyper-tensive antibleeding and antiswelling properties in additionto exhibiting anti-inflammatory characteristics Chemicallyit is an aglycone derived from an iridoid glycoside calledgeniposide that is enzymatically hydrolyzed to genipin byintestinal bacteria when administered per os [104] Genipinwas reported to inhibit mitochondrial uncoupling protein2 (UCP2) as well as superoxide-activated UCP2-mediatedproton leak occurring in a variety of diseases [105]
Recently it was shown that overexpression of UCP2caused a significant increase in NLRP3 expression in THP-1 cells and this was significantly inhibited by the adminis-tration of genipin while the levels of the adaptor proteinASC did not change [57] Interestingly genipin treatmentattenuated IL-1120573 levels in LPS-primed cells treated with ATPhowever this effect was not observed in cells treated withnigericin In addition it was also shown that inhibition ofATP-mediated inflammasome activation by genipin does notalter the production of other proinflammatory cytokines suchas IL-6 and TNF120572
In another recent study in LPS-primed murine BMDMsgenipin dramatically inhibited IL-1120573 secretion of LPS-primedcells following ATP nigericin MSU crystals or Listeriamonocytogenes treatment [58] Furthermore genipin alsoinhibited the Salmonella typhimurium-induced secretion ofIL-1120573 which is mediated via the activation of NLRC4inflammasome Similar to the previous study LPS-dependentTNF120572 secretion was not impaired by genipin Importantlygenipin treatment did not inhibit the expression of pro-IL-1120573 pro-caspase-1 or ASC proteins however it inhibitedNLRP3-dependent ASC oligomerization in addition to IL-1120573secretion and caspase-1 activation In contrast to its inhibitoryeffect on NLRP3-mediated ASC oligomerization genipindid not affect NLRC4-mediated formation of ASC speckleswhileNLRC4-mediated caspase-1 activationwas significantlydiminished These data indicate that the inhibitory effect ofgenipin on NLRC4 inflammasome activation is independentof ASC
45 Ginseng White ginseng is the naturally dried formof ginseng (Panax ginseng) while red ginseng is made bysteaming and drying fresh ginseng root Red ginseng hasbeen used for centuries as an immune-modulator and hasalso been used as an adjuvant in the treatment of infectiousand metabolic diseases Korean red ginseng contains variousactive components including saponins such as ginsenosidesand nonsaponins such as polysaccharides peptides fattyacids and mineral oils Ginsenosides are the major activecomponents of ginseng They reduce the production ofinflammatory cytokines by inhibiting NF120581B signaling [106]They also have amphiphilic nature and are able to intercalateinto the plasma membrane and influence membrane fluidityand function
It was shown that red ginseng extract (RGE) inhibitedATP- nigericin- and aluminum-induced IL-1120573 secretionin LPS-primed BMDMs and THP-1 cells and amelioratedlethality in LPS-induced septic shock model of mice [59]Furthermore RGE attenuated IL-1120573 secretion in dsDNA-transfected macrophages Similar results were obtained for
ginsenosides Furthermore it was also shown that RGE actedas an inhibitor of both NLRP3 and AIM2 inflammasomeactivations It was also demonstrated that RGE attenuated thesecretion of the active form of caspase-1 (p20)
It was previously reported that endogenousNOproducedby iNOS inhibits NLRP3 inflammasome activation via theS-nitrosylation of NLRP3 protein [107 108] A recent studyreported that ginsenosides negatively regulates LPS-inducedseptic shock in mice by a mechanism involving inhibitionof iNOS expression and the subsequent NO production[60] It was shown that ginsenosides reduced NO leveliNOS expression and ROS level in peritoneal macrophagesand BMDMs after LPS stimulation They also found thatginsenoside treatment attenuated S-nitrosylation of NLRP3protein which resulted in increased IL-beta secretion in LPS-activated macrophages
46 Mangiferin Mangiferin is a water-soluble naturalpolyphenol with a C-glycosylxanthone structure The pri-mary source of mangiferin is the mango tree (Mangiferaindica) however it is also present in some medicinal herbsin Iris unguicularis and in the honeybush a popular herbaltea from South Africa It possesses a wide spectrum ofbeneficial effects on health being used as an analgesicantidiabetic antisclerotic antimicrobial and antiviral as wellas being praised for its anti-inflammatory effects It has beenshown to regulate AMPK activity and in a recent work itwas reported that in human endothelial cells exposed tohigh glucose mangiferin reduced IL-1120573 secretion [61] Fur-thermore mangiferin attenuated IRE1 phosphorylation andreducedROS production and it decreased TXNIP expressionand inhibited ER stress Moreover a decrease in NLRP3expression and IL-1120573 production was also demonstrated
Very recently the protective role of mangiferin wasdescribed in LPS plus D-galactosamine- (D-GalN-) inducedacute liver injury [62] The authors showed that mangiferinreduced IL-1120573 secretion and ROS production and it alsoinhibited iNOS expression but induced Nrf2 and HO-1expression Furthermore it attenuated NLRP3 ASC andcaspase-1 (p10) expression and the subsequent IL-1120573 produc-tion
47 Propolis Propolis is a resinous material produced bybees (Apis mellifera L) through the mixing of secretions andenzymes from their hypopharyngeal glands with the budsof plants and wax A few hundred compounds have beendetected in raw propolis including polyphenols terpenoidssteroids sugar and amino acids Propolis composition islargely influenced by botanical origins and geographicallocation as well as by collection season One of the mostknown biological activities of propolis is related to its anti-inflammatory effect Artepillin C is a simple phenol com-posed of a single ring with two prenyl groups (35-diprenyl-4-hydroxycinnamic acid) and is the major biologically activephenolic ingredient identified in green propolis derived fromSoutheast Brazil [109]
The role of artepillin C was studied on the oxidativemetabolism of PMA-stimulated RAW2647 macrophages[63] It was shown that artepillin C significantly inhibited
Mediators of Inflammation 9
ROS release upon the NLRP3 activator nigericin treatment Itwas also suggested that artepillin C significantly contributedto the modulation of chemokine-mediated inflammation asit significantly downregulated the release of IL-1120573 IL-12p40and TNF120572 by LPS + IFN120574-treated RAW2647 cells whereasthe synthesis of IL-1120572 and IL-6 was not affected Besidesnigericin-mediated IL-1120573 production propolis also inhibitedLegionella pneumophila-induced IL-1120573 cytokine secretionin LPS-primed BMDMs This indicates that both NLRP3and NLRC4 inflammasome functions may be regulated bypropolis however further studies are required to clarify thedetailed molecular mechanism of the observed results
48 Quercetin Quercetin a kind of flavonoid found in avariety of vegetables beverages fruits and herbs exhibitsanti-inflammatory and antioxidant properties Quercetinwasreported to reduce inflammation in visceral adipose tissueprimary human adipocytes and the kidney of fructose-fedrats It was also shown to prevent diabetic kidney injury inratsHowever themechanisms of the action of quercetinwerenot clarified
It has been described that quercetin attenuated fructose-induced hyperuricemia and renal dysfunction In a studyusing streptozotocin- (STZ-) induced diabetic nephropa-thy rat model leading to hyperuricemia and dyslipidemiaquercetin was found to block NLRP3 inflammasome acti-vation [64] It was shown that the STZ-induced expres-sion of inflammasome components was restrained and IL-1120573 secretion was reduced by quercetin treatment Similarresults were obtained studying inflammatory responses infructose-induced hyperuricemia in rat [65] They showedthat fructose significantly elevated the expression of renalNLRP3 ASC and caspase-1 expression while quercetintreatment ameliorated the expression of these proteins Basedon their findings it was suggested that fructose-mediatedrenal NLRP3 inflammasome activation and proinflamma-tory cytokine overproduction may be associated with theimpaired cross talk between renal JAK2-STAT3 and PPAR-120572signaling pathway that in turn regulate renal inflammation
Furthermore it was shown that quercetin markedlyinhibited the overexpression of hepatic TXNIP in additionto reducing the production of ROS and the activation ofNLRP3 inflammasome consequently resulting in decreasedIL-1120573 secretion [66 110]They also showed that the decreasedcaspase-1 activity downregulated the caspase-1-dependentactivation of SREBPs that are involved in fatty acid andcholesterol synthesis They suggested that regulation of theTXNIP-NLRP3-SREBPs pathway by quercetin may partiallymediate the alleviation of hepatic steatosis in these diabeticrats
It was also shown that quercetin treatment regulatedAMPK pathway activation glutamine-glutamate cycle dys-function and TXNIP overexpression moreover it sup-pressed NF120581B pathway eventually leading to impairedNLRP3 inflammasome activation and IL-1120573 production inthe hypothalamus of high fructose- (HF-) fed rats [67]
Using human umbilical vein endothelial cells anothergroup reported that quercetin suppressed palmitate- (PA-) induced IL-1120573 and IL-6 induction [68] Downregulation
of NLRP3 induction was probably partially mediated viathe inhibition of ROS production and TXNIP expressionquercetin also inhibited IKK120573 activation by attenuatingits phosphorylation Furthermore quercetin treatment pro-tected cells against PA insult and significantly reduced thenumber of apoptotic cells Moreover quercetin amelioratedER stress-induced endothelial dysfunction through the acti-vation of AMPK
NLRP3 inflammasome is also recognized to have animportant role in the spinal cord tissue after traumatic spinalcord injury (SCI) and targeting the NLRP3 inflammasomecan inhibit neuroinflammation thereby improving func-tional recovery in SCI rats [111]
Very recently in a ratmodel of SCI quercetin administra-tion was shown to significantly improve functional recovery[69] Histopathological changes of the spinal cord such ascongestion edema neutrophil infiltration and structuraldisruption were inhibited by quercetin administration Toformulate a molecular mechanism the authors showed thatquercetin administration significantly reduced inflammatorycytokine IL-1120573 IL-18 and TNF120572 levels it also reduced theNLRP3 ASC and active caspase-1 protein expression andROS production However further studies are needed tobetter characterize the mechanisms of action underlying thebeneficial effects of quercetin in inflammation and immunity
49 Resveratrol Resveratrol is a polyphenol present inthe skin of grapes and mulberry commonly used in redwine production The beneficial effects of resveratrol arethought to be mediated in part by its antioxidant andanti-inflammatory properties exhibiting beneficial effectsin several diseases [112] Resveratrol exists as two isomerscis- and trans-resveratrol The cis isomer is thought to beproduced naturally during grape fermentation as a resultof isomerization of the trans isomer by yeast isomerasesFurthermore cis-resveratrol can be obtained by exposure ofthe trans isomer to sunlight Several studies have shown thattrans-resveratrol exhibits a wide range of biological activitiesincluding anti-inflammatory antioxidant anticarcinogenicantiaging antiplatelet aggregation immune-modulatory andchemoprevention effects However only few studies havebeen performed to examine the biological effects of the cisisomer Studies on cis-resveratrol have demonstrated thatit also possesses anticancer antimicrobial and antiplateletaggregation activities
One of the biological roles of resveratrol is to initiate theactivation of sirtuin 1 (Sirt1) is a deacetylase that modifies andinactivates inflammatory genes At high doses resveratrolhas been shown to activate AMPK which is involved inthe negative regulation of the NLRP3-inflammasome [113]It was also shown that ionizing radiation-induced IL-1120573secretion by human mesenchymal stem cells (MSCs) aneffect that was effectively abrogated by pretreatment withresveratrol [70] Radiation-induced increase in IL-1120573 occursvia the NLRP3 inflammasome activation however resver-atrol treatment attenuated the expression of NLRP3 It wasalso demonstrated that resveratrol treatment upregulated theexpression of Sirt1 In conclusion it is suggested that Sirt1
10 Mediators of Inflammation
inhibits NF120581B transcriptional activity through deacetylationthat in turn limits the transcription of NLRP3
In another study it was shown that cis-resveratrol pre-treatment significantly inhibited IL-1120573 secretion in THP-1 cellculture supernatants interestingly cis-resveratrol inducedIL-18 secretion under these conditions [71] Accordingly cis-resveratrol significantly reduced IL-1120573 mRNA expressionin contrast cis-resveratrol used at the same concentra-tion increased IL-18 mRNA expression Furthermore cis-resveratrol increased the mRNA and protein levels of NLRP1and NLRP3 indicating that the inhibitory effect of cis-resveratrol on IL-1120573 secretion is not due to the down-regulation of NLRP1 NLRP3 or ASC expression Similarresults were obtained on LPS-primed J774A1 macrophageswhere resveratrol inhibited the ATP-induced IL-1120573 secretionhowever in this study the authors did not find changes in theexpression of NLRP3 [72] showing that the resveratrol didnot inhibit the priming signal of NLRP3
Huang et al suggested that the inhibitory effect of cis-resveratrol on IL-1120573 secretion may be due to the reducedexpression of purinergic receptor P2X7R and the ER stressmarker GRP78 which leads to suppression of ROS pro-duction and reduced caspase-1 and caspase-4 activation Itwas found that cis-resveratrol also inhibited cyclooxygenase-(COX-) 2 expression which may be responsible for theobserved decrease of PGE2 production Furthermore inhi-bition of pro-IL-1120573 and COX-2 expression may occur bydownregulating the activation of the p38 MAPK path-way [71] Importantly in contrast to these observationsincreased phosphorylation of p38 was detected in ATP-activated J774A1 macrophages by Chang et al while itdid not significantly increase the phosphorylation levelsof ERK12 and it reduced the phosphorylation levels ofJNK12 The levels of mtDNA release into the cytosol weresignificantly reduced by resveratrol indicating that therewas less mitochondrial injury in resveratrol-treated cells[72] Furthermore the authors also showed that resveratrolincreased cellular cAMP level in J774A1 macrophages whichacts as a negative regulator of inflammatory responses andinhibits NLRP3 inflammasome activation
The effect of resveratrol on NLRP3 inflammasome wasfurther proved by a study showing that four weeks ofresveratrol administration inhibited the expression of NLRP3inflammasome components IL-1 IL-6 and TNF120572 and inlivers of HF-fed mice [73] They also showed that theregulatory effects of resveratrol on NLRP3 inflammasomemay come about through the combined effects of Sirt1 andSirt6
In a recent study [50] it was found that resveratroltreatment successfully suppressed the maturation of bothIL-1120573 and caspase-1 in response to Pam3CSK4 a TLR12agonist plus various inducers (like nigericin ATP MSUand silica) of the NLRP3-inflammasome In mouse BMDMshowever it did not affect the production of IL-1120573 medi-ated by the NLRC4-inflammasome (flagellin) or the AIM2-inflammasome (dsDNA) On a mouse model of acute goutthey indicated that resveratrol reduced the amount of matureIL-1120573 and the subsequent recruitment of neutrophils intothe peritoneal cavities of mice after challenge with MSU
crystals These findings indicate that resveratrol suppressesthe activation of the NLRP3-inflammasome both in vitroand in vivo As a possible mechanism they showed thatresveratrol at a substantially higher dosage successfullysuppressed mitochondrial ROS production Furthermoreresveratrol treatment prevented the accumulation of acety-lated 120572-tubulin thusinhibiting the proximate localization ofASC and NLRP3 in macrophages
In a very recent publication [74] the authors showed thatresveratrol preventedATP-inducedNLRP3 activation and IL-1120573 production in the BV2 cell line and in septic mice as wellThey also found that resveratrol treatment reduced NLRP3and IL-1120573 expression in the hippocampus of the mice andthey suggested that the protecting effect of resveratrol wasmediated via the increased expression of Sirt1 in BV2 cells
Another recent publication found that glucose-basedperitoneal dialysis increased mitochondrial ROS productionand subsequent IL-1120573 secretion through NLRP3 inflamma-some in human peritoneal mesothelial cells (HPMC) Asa mechanism for its action they showed that resveratrolinduced mitophagyautophagy of the cells via AMPK activa-tion and protected cells fromROS-inducedNLRP3-mediatedinflammatory injury [75]
410 Sulforaphane Sulforaphane (SFN) is a natural com-pound present in cruciferous vegetables such as broccolicabbage Brussel sprouts mustard and radish ChemicallySFN is an isothiocyanate that is known to react withsulfhydryl groups and tomodify proteins at cysteine residuesSulforaphane is produced from the precursor glucoraphaninby the enzymatic activity of myrosinase when the cell wallsof the plant are damaged for example during chewingSFN has been known as a cytoprotective agent for cancerprevention or treatment and it also has an important rolein cardiovascular neurologic and other diseases (reviewedin [114]) SFN is a known inducer of the Nrf2 antioxidantpathway as it activates the Nrf2 transcription factor byreacting with cysteine residues of its repressor Keap1 [115]In addition it also inhibits NF120581B signaling [116]
It was shown that SFN inhibited IL-1120573 processing byNLRP1- NLRP3- NLRC4- and AIM2- inflammasome com-plexes in mouse BMDMs [28] It was also demonstratedthat SFN inhibits the inflammasome in an Nrf2-independentmanner as SFN-mediated inhibition of NLRP3- andNLRC4-dependent IL-1120573 processing and secretion was not reversedin Nrf2-knockout BMDMs When SFN was added directlyto the cell lysates it did not inhibit IL-1120573 processingdemonstrating that SFN does not directly inhibit the proteaseactivity of caspase-1 The authors found that SFN-mediatedinhibition of the inflammasomes is not affected by ROSmodulation and neither proteasome-dependent proteolysisnor de novo protein synthesis is required for SFN-mediatedinhibition of the inflammasomes In a peritonitis model ofacute gout SFN treatment significantly reducedMSU crystal-induced IL-1120573 production demonstrating that SFN inhibitsthe NLRP3 inflammasome function in vivo Nonethelessthe authors concluded that SFN inhibits multiple inflam-masomes in vitro and in vivo by a mechanism independent
Mediators of Inflammation 11
ERKp38
NLRP3
ASCNLRP3
Caspase-1ROS
ER stress
P2X7R ATP
Cathepsin B
TLR
ROS
mtDNA
Sirt2
AcAc
AcAc
AMPK
A
A AC
C
C
Nrf2E
E
UCP2Ge
Ge
Ge
Gi
TXNIPC
NOGi
P
Sirt1R
R
R
R
M
M
M
Q
QQ
SS
S
R
Cardio-lipin
Acetylated 120572-tubulin
Ca2+ influx
IL-1120573
Pro-IL-1120573
K+efflux
120572-Tubulin
Pro-IL-1120573
NF120581B
Figure 3 Molecular targets of natural compounds affecting NLRP3 inflammasome-mediated IL-1 production
of inflammasome priming and Nrf2 signaling however theexact molecular mechanism was not explored
As SFN is able to penetrate the blood-brain barrier[117] it gained a considerable attention as a candidatefor Alzheimerrsquos disease (AD) therapy SFN was shown toprotect the brain from A120573-induced oxidative cell death viaactivation of Nrf2 signaling cascade [118] As A120573 fibrilshave been shown to activate NLRP3 inflammasome thequestion arose whether SFN may regulate this mechanismIn a very recent study it was shown that SFN significantlydownregulated IL-1120573 production and NLRP3 expression inA1205731ndash42 peptide-stimulated human THP-1 cells macrophages[76] It was found that A1205731ndash42 peptide-induced STAT-1phosphorylation was significantly attenuated by SFN Theauthors showed that SFN inducedNrf2 nuclear translocationwhich was subsequently accompanied by an increase in HO-1 protein levels Furthermore A1205731ndash42 peptide-induced IL-1120573 production was diminished by siRNA-mediated knock-down of Nrf2 or HO-1 They also found that the increasedproinflammatory miRNA-146a level following A1205731ndash42 treat-ment was significantly attenuated by SFN whereas miRNA-125b and miRNA-155 levels were not changed These arespecific proinflammatory miRNAs that were reported to beincreased in both the extracellular fluid and cerebrospinalfluid of AD patients In conclusion SFN can suppress A1205731ndash42-induced caspase-1-dependent inflammasome activationpossibly through inhibiting STAT-1 phosphorylation andactivation of the Nrf2HO-1 signaling pathway
Also very recently another research group reported thatoral administrations of SFN suppressed the saturated fattyacid-induced NLRP3 inflammasome activation in the liverof mice [77] They found that SFN decreased the expression
of ASC caspase-1 and IL-1120573 levels additionally it inhibitedthe activity of caspase-1 enzyme in primary hepatocytes Itwas also shown that SFN reduced the palmitate-inducedROS production by the mitochondria implying that SFNprevented mitochondrial dysfunction and this protectingmechanism was in part mediated by the activation of AMPKThey concluded that activation of AMPK and autophagy bySFN could protect from mitochondrial dysfunction inducedby saturated fatty acids resulting in a downregulation of fat-induced activation of the NLRP3 inflammasome
5 NLRP3 Inflammasome and theXenohormesis Hypothesis
As it was described in detail above polyphenols like resvera-trol curcumin EGCG and quercetin are potent inhibitors ofNLRP3 inflammasome-mediated IL-1120573 production typicallyacting at more than one element of the involved pathways(Figure 3)However it should be noted that these polyphenolshave an evenmuch broader biological effect as they influencea variety of pathways [119] though not all are directlyconnected to the function of the NLRP3 inflammasomeImportantly more than 8000 natural polyphenols have beendescribed [120] providing a large library of compounds aspotential inflammasome inhibitors Many of these polyphe-nols (such as resveratrol and curcumin) are overproducedby stressed plants triggering pathways mimicking the effectof caloric restriction It has been proposed that organismsfrom yeast to humans consuming stressed plants couldinterpret the stress signal carried by such polyphenols as apotential risk of future limitation of food availability and in
12 Mediators of Inflammation
turn adapting for the pursuit of longevity a theory termedas Xenohormesis [121ndash123] Interestingly the structurallyunrelated resveratrol and curcumin can achieve this caloricrestriction mimicking effect by activating AMPK and Sirt1[124] However polyphenols are also known to have anantioxidant effect activate glutathione S-transferases andinhibit COX enzymes among many other effects [125 126]Interestingly one of the most frequently used COX inhibitoris aspirin a derivative of another stress-induced phytochem-ical salicylic acid
A major concern of polyphenol use in therapy is thebioavailability of these compounds Nevertheless typicaldietary polyphenol intake is about 14mgkgday which iswithin the range of providing biologically active doses [127]
6 Concluding Remarks
Most of the time inflammasome-mediated IL-1120573 productionor caspase-mediated pyroptosis is beneficial for the host as itprotects from infection or prevents further damageHoweverprolonged cytokine production as in the case of sterileinflammation caused by endogenous danger signals maylead to the development of autoinflammatory or metabolicdiseases Chronic inflammation compromises the hostrsquos lifequality and requires sustained pharmacological and surgicaltreatments The paradigm of drug discovery in Westernmedicine is to develop highly selective compounds againstindividual druggable targets Currently the main treatmentmethods for these patients are targeting IL-1120573 Howeverprolonged usage of drugs may induce different side effectsfurthermore some form of medications are very expensivewhich limits their widespread use
Besides the high expenses another drawback of tradi-tional drug design is that many of the promising compoundsfail in the early or later stages of drug development Tradi-tional medicine uses many plant products to treat diseaseshowever the exact mechanisms behind their use is stillmostly lacking partially as a consequence of the pleiotropiceffect of the active compounds as detailed in this reviewNevertheless clarification of the molecular mechanism ofaction of such natural compounds already used in traditionalmedicine for quite some time will undoubtedly aid in theproduction of safe and cheap candidate medications to beused in the treatment of diseases including those appearingas a consequence of NLRP3 inflammasome-mediated IL-1120573overproduction
Competing Interests
The authors declare no conflict of interests
Acknowledgments
This work was supported by OTKA-K 109429 Szilvia Benkois a receiver of Lajos Szodoray Postdoctoral Fellowship andJanos Bolyai Postdoctoral Fellowship
References
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[2] G Meng F Zhang I Fuss A Kitani and W Strober ldquoA muta-tion in the Nlrp3 gene causing inflammasome hyperactivationpotentiates Th17 cell-dominant immune responsesrdquo Immunityvol 30 no 6 pp 860ndash874 2009
[3] D Lasiglie E Traggiai S Federici et al ldquoRole of IL-1 beta in thedevelopment of human TH17 cells lesson fromNLPR3mutatedpatientsrdquo PLoS ONE vol 6 no 5 Article ID e20014 2011
[4] H Schneider F Pitossi D Balschun A Wagner A Del Reyand H O Besedovsky ldquoA neuromodulatory role of interleukin-1120573 in the hippocampusrdquo Proceedings of the National Academy ofSciences of the United States of America vol 95 no 13 pp 7778ndash7783 1998
[5] E Gabay G Wolf Y Shavit R Yirmiya and M Tal ldquoChronicblockade of interleukin-1 (IL-1) prevents and attenuates neuro-pathic pain behavior and spontaneous ectopic neuronal activityfollowing nerve injuryrdquo European Journal of Pain vol 15 no 3pp 242ndash248 2011
[6] A del Rey A V Apkarian M Martina and H O BesedovskyldquoChronic neuropathic pain-like behavior and brain-borne IL-1120573rdquo Annals of the New York Academy of Sciences vol 1262 no 1pp 101ndash107 2012
[7] R Yirmiya and I Goshen ldquoImmune modulation of learningmemory neural plasticity and neurogenesisrdquo Brain Behaviorand Immunity vol 25 no 2 pp 181ndash213 2011
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[14] F Martinon V Petrilli A Mayor A Tardivel and J TschoppldquoGout-associated uric acid crystals activate the NALP3 inflam-masomerdquo Nature vol 440 no 7081 pp 237ndash241 2006
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[26] K Shimada T R Crother J Karlin et al ldquoOxidized mito-chondrial DNA activates the NLRP3 inflammasome duringapoptosisrdquo Immunity vol 36 no 3 pp 401ndash414 2012
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[37] D Perregaux and C A Gabel ldquoInterleukin-1 beta maturationand release in response to ATP and nigericin Evidence thatpotassium depletion mediated by these agents is a necessaryand common feature of their activityrdquoThe Journal of BiologicalChemistry vol 269 no 21 pp 15195ndash15203 1994
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[41] T Murakami J Ockinger J Yu et al ldquoCritical role for calciummobilization in activation of the NLRP3 inflammasomerdquo Pro-ceedings of the National Academy of Sciences of the United Statesof America vol 109 no 28 pp 11282ndash11287 2012
[42] V Hornung F Bauernfeind A Halle et al ldquoSilica crystals andaluminum salts activate the NALP3 inflammasome throughphagosomal destabilizationrdquo Nature Immunology vol 9 no 8pp 847ndash856 2008
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[45] X Wang W Jiang Y Yan et al ldquoRNA viruses promoteactivation of the NLRP3 inflammasome through a RIP1-RIP3-DRP1 signaling pathwayrdquoNature Immunology vol 15 no 12 pp1126ndash1133 2014
[46] T Ichinohe T Yamazaki T Koshiba and Y Yanagi ldquoMitochon-drial protein mitofusin 2 is required for NLRP3 inflammasomeactivation afterRNAvirus infectionrdquoProceedings of theNationalAcademy of Sciences of the United States of America vol 110 no44 pp 17963ndash17968 2013
[47] N Subramanian K Natarajan M R Clatworthy Z Wangand R N Germain ldquoThe adaptor MAVS promotes NLRP3mitochondrial localization and inflammasome activationrdquo Cellvol 153 no 2 pp 348ndash361 2013
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14 Mediators of Inflammation
moleculesrdquo ACS Chemical Biology vol 8 no 12 pp 2724ndash27332013
[49] K Nakahira J A Haspel V A K Rathinam et al ldquoAutophagyproteins regulate innate immune responses by inhibiting therelease of mitochondrial DNA mediated by the NALP3 inflam-masomerdquo Nature Immunology vol 12 no 3 pp 222ndash230 2011
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[51] M M Budai A Varga S Milesz J Tozser and S BenkoldquoAloe vera downregulates LPS-induced inflammatory cytokineproduction and expression of NLRP3 inflammasome in humanmacrophagesrdquo Molecular Immunology vol 56 no 4 pp 471ndash479 2013
[52] J-W Han D-W Shim W-Y Shin et al ldquoAnti-inflammatoryeffect of emodin via attenuation of NLRP3 inflammasomeactivationrdquo International Journal of Molecular Sciences vol 16no 4 pp 8102ndash8109 2015
[53] Y Li J Li S Li et al ldquoCurcumin attenuates glutamate neurotox-icity in the hippocampus by suppression of ER stress-associatedTXNIPNLRP3 inflammasome activation in a manner depen-dent onAMPKrdquoToxicology andApplied Pharmacology vol 286no 1 pp 53ndash63 2015
[54] Z Gong J Zhou H Li et al ldquoCurcumin suppresses NLRP3inflammasome activation and protects against LPS-inducedseptic shockrdquo Molecular Nutrition and Food Research vol 59no 11 pp 2132ndash2142 2015
[55] P-Y Tsai S-M Ka J-M Chang et al ldquoEpigallocatechin-3-gallate prevents lupus nephritis development in mice viaenhancing the Nrf2 antioxidant pathway and inhibiting NLRP3inflammasome activationrdquo Free Radical Biology and Medicinevol 51 no 3 pp 744ndash754 2011
[56] Z Gao Y Han Y Hu et al ldquoTargeting HO-1 byepigallocatechin-3-gallate reduces contrast-induced renalinjury via anti-oxidative stress and anti-inflammationpathwaysrdquo PLOS ONE vol 11 no 2 article e0149032 2016
[57] V Rajanbabu L Galam J Fukumoto et al ldquoGenipin suppressesNLRP3 inflammasome activation through uncoupling protein-2rdquo Cellular Immunology vol 297 no 1 pp 40ndash45 2015
[58] S-X Yu C-T DuW Chen et al ldquoGenipin inhibits NLRP3 andNLRC4 inflammasome activation via autophagy suppressionrdquoScientific Reports vol 5 article 17935 2015
[59] J Kim H Ahn B-C Han et al ldquoKorean red ginseng extractsinhibit NLRP3 and AIM2 inflammasome activationrdquo Immunol-ogy Letters vol 158 no 1-2 pp 143ndash150 2014
[60] S-J Yoon J-Y Park S Choi et al ldquoGinsenoside Rg3 regulatesS-nitrosylation of the NLRP3 inflammasome via suppression ofiNOSrdquo Biochemical and Biophysical Research Communicationsvol 463 no 4 pp 1184ndash1189 2015
[61] J Song J Li F Hou X Wang and B Liu ldquoMangiferininhibits endoplasmic reticulum stress-associated thioredoxin-interacting proteinNLRP3 inflammasome activation with reg-ulation of AMPK in endothelial cellsrdquo Metabolism vol 64 no3 pp 428ndash437 2015
[62] C-W Pan Z-Z Pan J-J Hu et al ldquoMangiferin alleviateslipopolysaccharide and D-galactosamine-induced acute liverinjury by activating the Nrf2 pathway and inhibiting NLRP3inflammasome activationrdquo European Journal of Pharmacologyvol 770 pp 85ndash91 2016
[63] J I Hori D S Zamboni D B Carrao GHGoldman andAABerretta ldquoThe inhibition of inflammasome by Brazilian propo-lis (EPP-AF)rdquo Evidence-Based Complementary and AlternativeMedicine vol 2013 Article ID 418508 11 pages 2013
[64] C Wang Y Pan Q-Y Zhang F-M Wang and L-D KongldquoQuercetin and allopurinol ameliorate kidney injury in STZ-treated rats with regulation of renal NLRP3 inflammasomeactivation and lipid accumulationrdquo PLoS ONE vol 7 no 6Article ID e38285 2012
[65] Q-H Hu X Zhang Y Pan Y-C Li and L-D Kong ldquoAllop-urinol quercetin and rutin ameliorate renal NLRP3 inflamma-some activation and lipid accumulation in fructose-fed ratsrdquoBiochemical Pharmacology vol 84 no 1 pp 113ndash125 2012
[66] WWangCWangX-QDing et al ldquoQuercetin and allopurinolreduce liver thioredoxin-interacting protein to alleviate inflam-mation and lipid accumulation in diabetic ratsrdquo British Journalof Pharmacology vol 169 no 6 pp 1352ndash1371 2013
[67] Q-Y Zhang Y Pan R Wang et al ldquoQuercetin inhibitsAMPKTXNIP activation and reduces inflammatory lesions toimprove insulin signaling defect in the hypothalamus of highfructose-fed ratsrdquo Journal of Nutritional Biochemistry vol 25no 4 pp 420ndash428 2014
[68] J Wu X Xu Y Li et al ldquoQuercetin luteolin and epigallo-catechin gallate alleviate TXNIP and NLRP3-mediated inflam-mation and apoptosis with regulation of AMPK in endothelialcellsrdquo European Journal of Pharmacology vol 745 pp 59ndash682015
[69] W Jiang Y Huang N Han et al ldquoQuercetin suppresses NLRP3inflammasome activation and attenuates histopathology in a ratmodel of spinal cord injuryrdquo Spinal Cord vol 54 pp 592ndash5962016
[70] Y Fu Y Wang L Du et al ldquoResveratrol inhibits ionisingirradiation-induced inflammation in MSCs by activating Sirt1and limiting NLRP-3 inflammasome activationrdquo InternationalJournal ofMolecular Sciences vol 14 no 7 pp 14105ndash14118 2013
[71] T-T Huang H-C Lai Y-B Chen et al ldquoCis-Resveratrolproduces anti-inflammatory effects by inhibiting canonicaland non-canonical inflammasomes in macrophagesrdquo InnateImmunity vol 20 no 7 pp 735ndash750 2014
[72] Y-P Chang S-M Ka W-H Hsu et al ldquoResveratrol inhibitsNLRP3 inflammasome activation by preserving mitochondrialintegrity and augmenting autophagyrdquo Journal of Cellular Physi-ology vol 230 no 7 pp 1567ndash1579 2015
[73] S J Yang and Y Lim ldquoResveratrol ameliorates hepaticmetaflammation and inhibits NLRP3 inflammasome activa-tionrdquoMetabolism vol 63 no 5 pp 693ndash701 2014
[74] D-M Sui Q Xie W-J Yi et al ldquoResveratrol protects againstsepsis-associated encephalopathy and inhibits the NLRP3IL-1 120573 axis in microgliardquo Mediators of Inflammation vol 2016Article ID 1045657 10 pages 2016
[75] J Wu X Li G Zhu Y Zhang M He and J Zhang ldquoTherole of Resveratrol-inducedmitophagyautophagy in peritonealmesothelial cells inflammatory injury via NLRP3 inflamma-some activation triggered bymitochondrial ROSrdquoExperimentalCell Research vol 341 no 1 pp 42ndash53 2016
[76] Y W An K A Jhang S Y Woo J L Kang and Y HChong ldquoSulforaphane exerts its anti-inflammatory effectagainst amyloid-120573 peptide via STAT-1 dephosphorylationand activation of Nrf2HO-1 cascade in human THP-1macrophagesrdquo Neurobiology of Aging vol 38 pp 1ndash10 2016
[77] G Yang H E Lee and J Y Lee ldquoA pharmacological inhibitorof NLRP3 inflammasome prevents non-alcoholic fatty liver
Mediators of Inflammation 15
disease in a mouse model induced by high fat dietrdquo ScientificReports vol 6 Article ID 24399 2016
[78] L Franchi R Munoz-Planillo and G Nunez ldquoSensing andreacting to microbes through the inflammasomesrdquo NatureImmunology vol 13 no 4 pp 325ndash332 2012
[79] S L Cassel and F S Sutterwala ldquoSterile inflammatory responsesmediated by the NLRP3 inflammasomerdquo European Journal ofImmunology vol 40 no 3 pp 607ndash611 2010
[80] M-S Tan J-T Yu T Jiang X-C Zhu and L Tan ldquoThe NLRP3inflammasome in alzheimerrsquos diseaserdquoMolecular Neurobiologyvol 48 no 3 pp 875ndash882 2013
[81] M Gold and J El Khoury ldquo120573-amyloid microglia andthe inflammasome in Alzheimerrsquos diseaserdquo Seminars inImmunopathology vol 37 no 6 pp 607ndash611 2015
[82] P M Peeters T N Perkins E F M Wouters B T Mossmanand N L Reynaert ldquoSilica induces NLRP3 inflammasomeactivation in human lung epithelial cellsrdquo Particle and FibreToxicology vol 10 no 1 article 3 2013
[83] H Watanabe O Gaide V Petrilli et al ldquoActivation of the IL-1120573-processing inflammasome is involved in contact hypersen-sitivityrdquo Journal of Investigative Dermatology vol 127 no 8 pp1956ndash1963 2007
[84] X Dai K Sayama M Tohyama et al ldquoMite allergen is adanger signal for the skin via activation of inflammasome inkeratinocytesrdquo Journal of Allergy and Clinical Immunology vol127 no 3 pp 806ndash814 2011
[85] A Varga M M Budai S Milesz A Bacsi J Tozser and SBenko ldquoRagweed pollen extract intensifies lipopolysaccharide-induced priming of NLRP3 inflammasome in humanmacrophagesrdquo Immunology vol 138 no 4 pp 392ndash4012013
[86] B Vandanmagsar Y-H Youm A Ravussin et al ldquoThe NLRP3inflammasome instigates obesity-induced inflammation andinsulin resistancerdquo Nature Medicine vol 17 no 2 pp 179ndash1892011
[87] H Wen D Gris Y Lei et al ldquoFatty acid-induced NLRP3-ASCinflammasome activation interferes with insulin signalingrdquoNature Immunology vol 12 no 5 pp 408ndash415 2011
[88] L Liang X Tan Q Zhou et al ldquoIL-1120573 triggered by pepti-doglycan and lipopolysaccharide through TLR24 and ROS-NLRP3 inflammasome- dependent pathways is involved inocular behcetrsquos diseaserdquo Investigative Ophthalmology and VisualScience vol 54 no 1 pp 402ndash414 2013
[89] S Rosengren H M Hoffman W Bugbee and D L BoyleldquoExpression and regulation of cryopyrin and related proteinsin rheumatoid arthritis synoviumrdquo Annals of the RheumaticDiseases vol 64 no 5 pp 708ndash714 2005
[90] J M Kahlenberg ldquoAnti-inflammatory panaceaThe expandingtherapeutics of interleukin-1 blockaderdquo Current Opinion inRheumatology vol 28 no 3 pp 197ndash203 2016
[91] C-H Chien M-J Lee H-C Liou H-H Liou and W-MFu ldquoLocal immunosuppressive microenvironment enhancesmigration of melanoma cells to lungs in DJ-1 knockout micerdquoPLoS ONE vol 10 no 2 Article ID e0115827 2015
[92] C Antonopoulos and G R Dubyak ldquoChemotherapy engagesmultiple pathways leading to IL-1120573 production by myeloidleukocytesrdquo OncoImmunology vol 3 no 1 Article ID e274992014
[93] E Ozaki M Campbell and S L Doyle ldquoTargeting the NLRP3inflammasome in chronic inflammatory diseases current per-spectivesrdquo Journal of Inflammation Research vol 8 pp 15ndash272015
[94] J H Hamman ldquoComposition and applications of Aloe vera leafgelrdquoMolecules vol 13 no 8 pp 1599ndash1616 2008
[95] L Langmead R J Makins and D S Rampton ldquoAnti-inflammatory effects of aloe vera gel in human colorectalmucosa in vitrordquo Alimentary Pharmacology and Therapeuticsvol 19 no 5 pp 521ndash527 2004
[96] N Yun C-H Lee and S-M Lee ldquoProtective effect of Aloe veraon polymicrobial sepsis inmicerdquo Food andChemical Toxicologyvol 47 no 6 pp 1341ndash1348 2009
[97] C S Yu F S Yu J K Chan et al ldquoAloe-emodin affects the levelsof cytokines and functions of leukocytes from Sprague-Dawleyratsrdquo In Vivo vol 20 no 4 pp 505ndash509 2006
[98] M Pulido-Moran J Moreno-Fernandez C Ramirez-Tortosaand M Ramirez-Tortosa ldquoCurcumin and healthrdquo Moleculesvol 21 no 3 article E264 2016
[99] Y-F Dong L-X Wang X Huang et al ldquoKir61 knock-down aggravates cerebral ischemiareperfusion-induced neuralinjury in micerdquo CNS Neuroscience and Therapeutics vol 19 no8 pp 617ndash624 2013
[100] P J Maier K Zemoura M A Acuna G E Yevenes HU Zeilhofer and D Benke ldquoIschemia-like oxygen and glu-cose deprivation mediates down-regulation of cell surface 120574-aminobutyric acidB receptors via the endoplasmic reticulum(ER) stress-induced transcription factor CCAATenhancer-binding protein (CEBP)-homologous protein (CHOP)rdquo TheJournal of Biological Chemistry vol 289 no 18 pp 12896ndash129072014
[101] H-Y Shin S-H Kim H-J Jeong et al ldquoEpigallocatechin-3-gallate inhibits secretion of TNF-120572 IL-6 and IL-8 through theattenuation of ERK and NF-120581B in HMC-1 cellsrdquo InternationalArchives of Allergy and Immunology vol 142 no 4 pp 335ndash3442007
[102] W P Pulskens L M Butter G J Teske et al ldquoNlrp3 preventsearly renal interstitial edema and vascular permeability inunilateral ureteral obstructionrdquo PLoS ONE vol 9 no 1 ArticleID e85775 2014
[103] S Kamath and C A Roobottom ldquoHyperdense pericardial effu-sion in dermatomyositis and contrast induced nephropathyrdquoEmergency Radiology vol 11 no 3 pp 177ndash179 2005
[104] T Akao K Kobashi and M Aburada ldquoEnzymic studies onthe animal and intestinal bacterial metabolism of geniposiderdquoBiological and Pharmaceutical Bulletin vol 17 no 12 pp 1573ndash1576 1994
[105] R Wang K C MoYung M H Zhang and K Poon ldquoUCP2-and non-UCP2-mediated electric current in eukaryotic cellsexhibits different propertiesrdquo Environmental Science and Pollu-tion Research vol 22 no 24 pp 19618ndash19631 2015
[106] J-M Lu Q Yao and C Chen ldquoGinseng compounds an updateon their molecular mechanisms and medical applicationsrdquoCurrent Vascular Pharmacology vol 7 no 3 pp 293ndash302 2009
[107] E Hernandez-Cuellar K Tsuchiya H Hara et al ldquoCuttingedge nitric oxide inhibits the NLRP3 inflammasomerdquo TheJournal of Immunology vol 189 no 11 pp 5113ndash5117 2012
[108] B B Mishra V A K Rathinam G W Martens et alldquoNitric oxide controls the immunopathology of tuberculosis byinhibiting NLRP3 inflammasome-dependent processing of IL-1120573rdquo Nature Immunology vol 14 no 1 pp 52ndash60 2013
[109] T Matsuno S-K Jung Y Matsumoto M Saito and JMorikawa ldquoPreferential cytotoxicity to tumor cells of 35-diprenyl-4-hydroxycinnamic acid (artepillin C) isolated frompropolisrdquo Anticancer Research vol 17 no 5A pp 3565ndash35681997
16 Mediators of Inflammation
[110] X Zhang J-H Zhang X-Y Chen et al ldquoReactive oxy-gen species-induced TXNIP drives fructose-mediated hepaticinflammation and lipid accumulation through NLRP3 inflam-masome activationrdquo Antioxidants and Redox Signaling vol 22no 10 pp 848ndash870 2015
[111] A Zendedel S Johann S Mehrabi et al ldquoActivation and reg-ulation of NLRP3 inflammasome by intrathecal application ofSDF-1a in a spinal cord injury modelrdquoMolecular Neurobiologyvol 53 no 5 pp 3063ndash3075 2016
[112] H Inoue and R Nakata ldquoResveratrol targets in inflammationrdquoEndocrineMetabolic and ImmuneDisordersmdashDrug Targets vol15 no 3 pp 186ndash195 2015
[113] S S Kulkarni and C Canto ldquoThe molecular targets of resver-atrolrdquo Biochimica et Biophysica Acta (BBA)mdashMolecular Basis ofDisease vol 1852 no 6 pp 1114ndash1123 2015
[114] C A Houghton R G Fassett and J S Coombes ldquoSul-foraphane translational research from laboratory bench toclinicrdquo Nutrition Reviews vol 71 no 11 pp 709ndash726 2013
[115] A T Dinkova-Kostova W D Holtzclaw R N Cole et alldquoDirect evidence that sulfhydryl groups of Keap1 are the sensorsregulating induction of phase 2 enzymes that protect againstcarcinogens and oxidantsrdquo Proceedings of the National Academyof Sciences of the United States of America vol 99 no 18 pp11908ndash11913 2002
[116] E Heiss C Herhaus K Klimo H Bartsch and C GerhauserldquoNuclear factor 120581B is a molecular target for sulforaphane-mediated anti-inflammatory mechanismsrdquo The Journal of Bio-logical Chemistry vol 276 no 34 pp 32008ndash32015 2001
[117] A Alfieri S Srivastava R C M Siow et al ldquoSulforaphanepreconditioning of the Nrf2HO-1 defense pathway protectsthe cerebral vasculature against blood-brain barrier disruptionand neurological deficits in strokerdquo Free Radical Biology andMedicine vol 65 pp 1012ndash1022 2013
[118] C Lee G H Park S-R Lee and J-H Jang ldquoAttenuation of120573 -amyloid-induced oxidative cell death by sulforaphane viaactivation of NF-E2-related factor 2rdquo Oxidative Medicine andCellular Longevity vol 2013 Article ID 313510 12 pages 2013
[119] E Barrajon-Catalan M Herranz-Lopez J Joven et al ldquoMolec-ular promiscuity of plant polyphenols in the management ofage-related diseases far beyond their antioxidant propertiesrdquoAdvances in Experimental Medicine and Biology vol 824 pp141ndash159 2014
[120] L Bravo ldquoPolyphenols chemistry dietary sources metabolismand nutritional significancerdquo Nutrition Reviews vol 56 no 11pp 317ndash333 1998
[121] D W Lamming J G Wood and D A Sinclair ldquoSmallmolecules that regulate lifespan evidence for xenohormesisrdquoMolecular Microbiology vol 53 no 4 pp 1003ndash1009 2004
[122] K T Howitz and D A Sinclair ldquoXenohormesis sensing thechemical cues of other speciesrdquo Cell vol 133 no 3 pp 387ndash3912008
[123] P L Hooper P L Hooper M Tytell and L Vıgh ldquoXeno-hormesis health benefits from an eon of plant stress responseevolutionrdquoCell Stress and Chaperones vol 15 no 6 pp 761ndash7702010
[124] B L Queen and T O Tollefsbol ldquoPolyphenols and agingrdquoCurrent Aging Science vol 3 no 1 pp 34ndash42 2010
[125] J A Baur and D A Sinclair ldquoTherapeutic potential of resvera-trol the in vivo evidencerdquo Nature Reviews Drug Discovery vol5 no 6 pp 493ndash506 2006
[126] R A Sharma A J Gescher and W P Steward ldquoCurcumin thestory so farrdquoEuropean Journal of Cancer vol 41 no 13 pp 1955ndash1968 2005
[127] K Milton ldquoMicronutrient intakes of wild primates are humansdifferentrdquo Comparative Biochemistry and Physiology Part AMolecular amp Integrative Physiology vol 136 no 1 pp 47ndash592003
to protect the liver and gallbladder It possesses antihyper-tensive antibleeding and antiswelling properties in additionto exhibiting anti-inflammatory characteristics Chemicallyit is an aglycone derived from an iridoid glycoside calledgeniposide that is enzymatically hydrolyzed to genipin byintestinal bacteria when administered per os [104] Genipinwas reported to inhibit mitochondrial uncoupling protein2 (UCP2) as well as superoxide-activated UCP2-mediatedproton leak occurring in a variety of diseases [105]
Recently it was shown that overexpression of UCP2caused a significant increase in NLRP3 expression in THP-1 cells and this was significantly inhibited by the adminis-tration of genipin while the levels of the adaptor proteinASC did not change [57] Interestingly genipin treatmentattenuated IL-1120573 levels in LPS-primed cells treated with ATPhowever this effect was not observed in cells treated withnigericin In addition it was also shown that inhibition ofATP-mediated inflammasome activation by genipin does notalter the production of other proinflammatory cytokines suchas IL-6 and TNF120572
In another recent study in LPS-primed murine BMDMsgenipin dramatically inhibited IL-1120573 secretion of LPS-primedcells following ATP nigericin MSU crystals or Listeriamonocytogenes treatment [58] Furthermore genipin alsoinhibited the Salmonella typhimurium-induced secretion ofIL-1120573 which is mediated via the activation of NLRC4inflammasome Similar to the previous study LPS-dependentTNF120572 secretion was not impaired by genipin Importantlygenipin treatment did not inhibit the expression of pro-IL-1120573 pro-caspase-1 or ASC proteins however it inhibitedNLRP3-dependent ASC oligomerization in addition to IL-1120573secretion and caspase-1 activation In contrast to its inhibitoryeffect on NLRP3-mediated ASC oligomerization genipindid not affect NLRC4-mediated formation of ASC speckleswhileNLRC4-mediated caspase-1 activationwas significantlydiminished These data indicate that the inhibitory effect ofgenipin on NLRC4 inflammasome activation is independentof ASC
45 Ginseng White ginseng is the naturally dried formof ginseng (Panax ginseng) while red ginseng is made bysteaming and drying fresh ginseng root Red ginseng hasbeen used for centuries as an immune-modulator and hasalso been used as an adjuvant in the treatment of infectiousand metabolic diseases Korean red ginseng contains variousactive components including saponins such as ginsenosidesand nonsaponins such as polysaccharides peptides fattyacids and mineral oils Ginsenosides are the major activecomponents of ginseng They reduce the production ofinflammatory cytokines by inhibiting NF120581B signaling [106]They also have amphiphilic nature and are able to intercalateinto the plasma membrane and influence membrane fluidityand function
It was shown that red ginseng extract (RGE) inhibitedATP- nigericin- and aluminum-induced IL-1120573 secretionin LPS-primed BMDMs and THP-1 cells and amelioratedlethality in LPS-induced septic shock model of mice [59]Furthermore RGE attenuated IL-1120573 secretion in dsDNA-transfected macrophages Similar results were obtained for
ginsenosides Furthermore it was also shown that RGE actedas an inhibitor of both NLRP3 and AIM2 inflammasomeactivations It was also demonstrated that RGE attenuated thesecretion of the active form of caspase-1 (p20)
It was previously reported that endogenousNOproducedby iNOS inhibits NLRP3 inflammasome activation via theS-nitrosylation of NLRP3 protein [107 108] A recent studyreported that ginsenosides negatively regulates LPS-inducedseptic shock in mice by a mechanism involving inhibitionof iNOS expression and the subsequent NO production[60] It was shown that ginsenosides reduced NO leveliNOS expression and ROS level in peritoneal macrophagesand BMDMs after LPS stimulation They also found thatginsenoside treatment attenuated S-nitrosylation of NLRP3protein which resulted in increased IL-beta secretion in LPS-activated macrophages
46 Mangiferin Mangiferin is a water-soluble naturalpolyphenol with a C-glycosylxanthone structure The pri-mary source of mangiferin is the mango tree (Mangiferaindica) however it is also present in some medicinal herbsin Iris unguicularis and in the honeybush a popular herbaltea from South Africa It possesses a wide spectrum ofbeneficial effects on health being used as an analgesicantidiabetic antisclerotic antimicrobial and antiviral as wellas being praised for its anti-inflammatory effects It has beenshown to regulate AMPK activity and in a recent work itwas reported that in human endothelial cells exposed tohigh glucose mangiferin reduced IL-1120573 secretion [61] Fur-thermore mangiferin attenuated IRE1 phosphorylation andreducedROS production and it decreased TXNIP expressionand inhibited ER stress Moreover a decrease in NLRP3expression and IL-1120573 production was also demonstrated
Very recently the protective role of mangiferin wasdescribed in LPS plus D-galactosamine- (D-GalN-) inducedacute liver injury [62] The authors showed that mangiferinreduced IL-1120573 secretion and ROS production and it alsoinhibited iNOS expression but induced Nrf2 and HO-1expression Furthermore it attenuated NLRP3 ASC andcaspase-1 (p10) expression and the subsequent IL-1120573 produc-tion
47 Propolis Propolis is a resinous material produced bybees (Apis mellifera L) through the mixing of secretions andenzymes from their hypopharyngeal glands with the budsof plants and wax A few hundred compounds have beendetected in raw propolis including polyphenols terpenoidssteroids sugar and amino acids Propolis composition islargely influenced by botanical origins and geographicallocation as well as by collection season One of the mostknown biological activities of propolis is related to its anti-inflammatory effect Artepillin C is a simple phenol com-posed of a single ring with two prenyl groups (35-diprenyl-4-hydroxycinnamic acid) and is the major biologically activephenolic ingredient identified in green propolis derived fromSoutheast Brazil [109]
The role of artepillin C was studied on the oxidativemetabolism of PMA-stimulated RAW2647 macrophages[63] It was shown that artepillin C significantly inhibited
Mediators of Inflammation 9
ROS release upon the NLRP3 activator nigericin treatment Itwas also suggested that artepillin C significantly contributedto the modulation of chemokine-mediated inflammation asit significantly downregulated the release of IL-1120573 IL-12p40and TNF120572 by LPS + IFN120574-treated RAW2647 cells whereasthe synthesis of IL-1120572 and IL-6 was not affected Besidesnigericin-mediated IL-1120573 production propolis also inhibitedLegionella pneumophila-induced IL-1120573 cytokine secretionin LPS-primed BMDMs This indicates that both NLRP3and NLRC4 inflammasome functions may be regulated bypropolis however further studies are required to clarify thedetailed molecular mechanism of the observed results
48 Quercetin Quercetin a kind of flavonoid found in avariety of vegetables beverages fruits and herbs exhibitsanti-inflammatory and antioxidant properties Quercetinwasreported to reduce inflammation in visceral adipose tissueprimary human adipocytes and the kidney of fructose-fedrats It was also shown to prevent diabetic kidney injury inratsHowever themechanisms of the action of quercetinwerenot clarified
It has been described that quercetin attenuated fructose-induced hyperuricemia and renal dysfunction In a studyusing streptozotocin- (STZ-) induced diabetic nephropa-thy rat model leading to hyperuricemia and dyslipidemiaquercetin was found to block NLRP3 inflammasome acti-vation [64] It was shown that the STZ-induced expres-sion of inflammasome components was restrained and IL-1120573 secretion was reduced by quercetin treatment Similarresults were obtained studying inflammatory responses infructose-induced hyperuricemia in rat [65] They showedthat fructose significantly elevated the expression of renalNLRP3 ASC and caspase-1 expression while quercetintreatment ameliorated the expression of these proteins Basedon their findings it was suggested that fructose-mediatedrenal NLRP3 inflammasome activation and proinflamma-tory cytokine overproduction may be associated with theimpaired cross talk between renal JAK2-STAT3 and PPAR-120572signaling pathway that in turn regulate renal inflammation
Furthermore it was shown that quercetin markedlyinhibited the overexpression of hepatic TXNIP in additionto reducing the production of ROS and the activation ofNLRP3 inflammasome consequently resulting in decreasedIL-1120573 secretion [66 110]They also showed that the decreasedcaspase-1 activity downregulated the caspase-1-dependentactivation of SREBPs that are involved in fatty acid andcholesterol synthesis They suggested that regulation of theTXNIP-NLRP3-SREBPs pathway by quercetin may partiallymediate the alleviation of hepatic steatosis in these diabeticrats
It was also shown that quercetin treatment regulatedAMPK pathway activation glutamine-glutamate cycle dys-function and TXNIP overexpression moreover it sup-pressed NF120581B pathway eventually leading to impairedNLRP3 inflammasome activation and IL-1120573 production inthe hypothalamus of high fructose- (HF-) fed rats [67]
Using human umbilical vein endothelial cells anothergroup reported that quercetin suppressed palmitate- (PA-) induced IL-1120573 and IL-6 induction [68] Downregulation
of NLRP3 induction was probably partially mediated viathe inhibition of ROS production and TXNIP expressionquercetin also inhibited IKK120573 activation by attenuatingits phosphorylation Furthermore quercetin treatment pro-tected cells against PA insult and significantly reduced thenumber of apoptotic cells Moreover quercetin amelioratedER stress-induced endothelial dysfunction through the acti-vation of AMPK
NLRP3 inflammasome is also recognized to have animportant role in the spinal cord tissue after traumatic spinalcord injury (SCI) and targeting the NLRP3 inflammasomecan inhibit neuroinflammation thereby improving func-tional recovery in SCI rats [111]
Very recently in a ratmodel of SCI quercetin administra-tion was shown to significantly improve functional recovery[69] Histopathological changes of the spinal cord such ascongestion edema neutrophil infiltration and structuraldisruption were inhibited by quercetin administration Toformulate a molecular mechanism the authors showed thatquercetin administration significantly reduced inflammatorycytokine IL-1120573 IL-18 and TNF120572 levels it also reduced theNLRP3 ASC and active caspase-1 protein expression andROS production However further studies are needed tobetter characterize the mechanisms of action underlying thebeneficial effects of quercetin in inflammation and immunity
49 Resveratrol Resveratrol is a polyphenol present inthe skin of grapes and mulberry commonly used in redwine production The beneficial effects of resveratrol arethought to be mediated in part by its antioxidant andanti-inflammatory properties exhibiting beneficial effectsin several diseases [112] Resveratrol exists as two isomerscis- and trans-resveratrol The cis isomer is thought to beproduced naturally during grape fermentation as a resultof isomerization of the trans isomer by yeast isomerasesFurthermore cis-resveratrol can be obtained by exposure ofthe trans isomer to sunlight Several studies have shown thattrans-resveratrol exhibits a wide range of biological activitiesincluding anti-inflammatory antioxidant anticarcinogenicantiaging antiplatelet aggregation immune-modulatory andchemoprevention effects However only few studies havebeen performed to examine the biological effects of the cisisomer Studies on cis-resveratrol have demonstrated thatit also possesses anticancer antimicrobial and antiplateletaggregation activities
One of the biological roles of resveratrol is to initiate theactivation of sirtuin 1 (Sirt1) is a deacetylase that modifies andinactivates inflammatory genes At high doses resveratrolhas been shown to activate AMPK which is involved inthe negative regulation of the NLRP3-inflammasome [113]It was also shown that ionizing radiation-induced IL-1120573secretion by human mesenchymal stem cells (MSCs) aneffect that was effectively abrogated by pretreatment withresveratrol [70] Radiation-induced increase in IL-1120573 occursvia the NLRP3 inflammasome activation however resver-atrol treatment attenuated the expression of NLRP3 It wasalso demonstrated that resveratrol treatment upregulated theexpression of Sirt1 In conclusion it is suggested that Sirt1
10 Mediators of Inflammation
inhibits NF120581B transcriptional activity through deacetylationthat in turn limits the transcription of NLRP3
In another study it was shown that cis-resveratrol pre-treatment significantly inhibited IL-1120573 secretion in THP-1 cellculture supernatants interestingly cis-resveratrol inducedIL-18 secretion under these conditions [71] Accordingly cis-resveratrol significantly reduced IL-1120573 mRNA expressionin contrast cis-resveratrol used at the same concentra-tion increased IL-18 mRNA expression Furthermore cis-resveratrol increased the mRNA and protein levels of NLRP1and NLRP3 indicating that the inhibitory effect of cis-resveratrol on IL-1120573 secretion is not due to the down-regulation of NLRP1 NLRP3 or ASC expression Similarresults were obtained on LPS-primed J774A1 macrophageswhere resveratrol inhibited the ATP-induced IL-1120573 secretionhowever in this study the authors did not find changes in theexpression of NLRP3 [72] showing that the resveratrol didnot inhibit the priming signal of NLRP3
Huang et al suggested that the inhibitory effect of cis-resveratrol on IL-1120573 secretion may be due to the reducedexpression of purinergic receptor P2X7R and the ER stressmarker GRP78 which leads to suppression of ROS pro-duction and reduced caspase-1 and caspase-4 activation Itwas found that cis-resveratrol also inhibited cyclooxygenase-(COX-) 2 expression which may be responsible for theobserved decrease of PGE2 production Furthermore inhi-bition of pro-IL-1120573 and COX-2 expression may occur bydownregulating the activation of the p38 MAPK path-way [71] Importantly in contrast to these observationsincreased phosphorylation of p38 was detected in ATP-activated J774A1 macrophages by Chang et al while itdid not significantly increase the phosphorylation levelsof ERK12 and it reduced the phosphorylation levels ofJNK12 The levels of mtDNA release into the cytosol weresignificantly reduced by resveratrol indicating that therewas less mitochondrial injury in resveratrol-treated cells[72] Furthermore the authors also showed that resveratrolincreased cellular cAMP level in J774A1 macrophages whichacts as a negative regulator of inflammatory responses andinhibits NLRP3 inflammasome activation
The effect of resveratrol on NLRP3 inflammasome wasfurther proved by a study showing that four weeks ofresveratrol administration inhibited the expression of NLRP3inflammasome components IL-1 IL-6 and TNF120572 and inlivers of HF-fed mice [73] They also showed that theregulatory effects of resveratrol on NLRP3 inflammasomemay come about through the combined effects of Sirt1 andSirt6
In a recent study [50] it was found that resveratroltreatment successfully suppressed the maturation of bothIL-1120573 and caspase-1 in response to Pam3CSK4 a TLR12agonist plus various inducers (like nigericin ATP MSUand silica) of the NLRP3-inflammasome In mouse BMDMshowever it did not affect the production of IL-1120573 medi-ated by the NLRC4-inflammasome (flagellin) or the AIM2-inflammasome (dsDNA) On a mouse model of acute goutthey indicated that resveratrol reduced the amount of matureIL-1120573 and the subsequent recruitment of neutrophils intothe peritoneal cavities of mice after challenge with MSU
crystals These findings indicate that resveratrol suppressesthe activation of the NLRP3-inflammasome both in vitroand in vivo As a possible mechanism they showed thatresveratrol at a substantially higher dosage successfullysuppressed mitochondrial ROS production Furthermoreresveratrol treatment prevented the accumulation of acety-lated 120572-tubulin thusinhibiting the proximate localization ofASC and NLRP3 in macrophages
In a very recent publication [74] the authors showed thatresveratrol preventedATP-inducedNLRP3 activation and IL-1120573 production in the BV2 cell line and in septic mice as wellThey also found that resveratrol treatment reduced NLRP3and IL-1120573 expression in the hippocampus of the mice andthey suggested that the protecting effect of resveratrol wasmediated via the increased expression of Sirt1 in BV2 cells
Another recent publication found that glucose-basedperitoneal dialysis increased mitochondrial ROS productionand subsequent IL-1120573 secretion through NLRP3 inflamma-some in human peritoneal mesothelial cells (HPMC) Asa mechanism for its action they showed that resveratrolinduced mitophagyautophagy of the cells via AMPK activa-tion and protected cells fromROS-inducedNLRP3-mediatedinflammatory injury [75]
410 Sulforaphane Sulforaphane (SFN) is a natural com-pound present in cruciferous vegetables such as broccolicabbage Brussel sprouts mustard and radish ChemicallySFN is an isothiocyanate that is known to react withsulfhydryl groups and tomodify proteins at cysteine residuesSulforaphane is produced from the precursor glucoraphaninby the enzymatic activity of myrosinase when the cell wallsof the plant are damaged for example during chewingSFN has been known as a cytoprotective agent for cancerprevention or treatment and it also has an important rolein cardiovascular neurologic and other diseases (reviewedin [114]) SFN is a known inducer of the Nrf2 antioxidantpathway as it activates the Nrf2 transcription factor byreacting with cysteine residues of its repressor Keap1 [115]In addition it also inhibits NF120581B signaling [116]
It was shown that SFN inhibited IL-1120573 processing byNLRP1- NLRP3- NLRC4- and AIM2- inflammasome com-plexes in mouse BMDMs [28] It was also demonstratedthat SFN inhibits the inflammasome in an Nrf2-independentmanner as SFN-mediated inhibition of NLRP3- andNLRC4-dependent IL-1120573 processing and secretion was not reversedin Nrf2-knockout BMDMs When SFN was added directlyto the cell lysates it did not inhibit IL-1120573 processingdemonstrating that SFN does not directly inhibit the proteaseactivity of caspase-1 The authors found that SFN-mediatedinhibition of the inflammasomes is not affected by ROSmodulation and neither proteasome-dependent proteolysisnor de novo protein synthesis is required for SFN-mediatedinhibition of the inflammasomes In a peritonitis model ofacute gout SFN treatment significantly reducedMSU crystal-induced IL-1120573 production demonstrating that SFN inhibitsthe NLRP3 inflammasome function in vivo Nonethelessthe authors concluded that SFN inhibits multiple inflam-masomes in vitro and in vivo by a mechanism independent
Mediators of Inflammation 11
ERKp38
NLRP3
ASCNLRP3
Caspase-1ROS
ER stress
P2X7R ATP
Cathepsin B
TLR
ROS
mtDNA
Sirt2
AcAc
AcAc
AMPK
A
A AC
C
C
Nrf2E
E
UCP2Ge
Ge
Ge
Gi
TXNIPC
NOGi
P
Sirt1R
R
R
R
M
M
M
Q
QQ
SS
S
R
Cardio-lipin
Acetylated 120572-tubulin
Ca2+ influx
IL-1120573
Pro-IL-1120573
K+efflux
120572-Tubulin
Pro-IL-1120573
NF120581B
Figure 3 Molecular targets of natural compounds affecting NLRP3 inflammasome-mediated IL-1 production
of inflammasome priming and Nrf2 signaling however theexact molecular mechanism was not explored
As SFN is able to penetrate the blood-brain barrier[117] it gained a considerable attention as a candidatefor Alzheimerrsquos disease (AD) therapy SFN was shown toprotect the brain from A120573-induced oxidative cell death viaactivation of Nrf2 signaling cascade [118] As A120573 fibrilshave been shown to activate NLRP3 inflammasome thequestion arose whether SFN may regulate this mechanismIn a very recent study it was shown that SFN significantlydownregulated IL-1120573 production and NLRP3 expression inA1205731ndash42 peptide-stimulated human THP-1 cells macrophages[76] It was found that A1205731ndash42 peptide-induced STAT-1phosphorylation was significantly attenuated by SFN Theauthors showed that SFN inducedNrf2 nuclear translocationwhich was subsequently accompanied by an increase in HO-1 protein levels Furthermore A1205731ndash42 peptide-induced IL-1120573 production was diminished by siRNA-mediated knock-down of Nrf2 or HO-1 They also found that the increasedproinflammatory miRNA-146a level following A1205731ndash42 treat-ment was significantly attenuated by SFN whereas miRNA-125b and miRNA-155 levels were not changed These arespecific proinflammatory miRNAs that were reported to beincreased in both the extracellular fluid and cerebrospinalfluid of AD patients In conclusion SFN can suppress A1205731ndash42-induced caspase-1-dependent inflammasome activationpossibly through inhibiting STAT-1 phosphorylation andactivation of the Nrf2HO-1 signaling pathway
Also very recently another research group reported thatoral administrations of SFN suppressed the saturated fattyacid-induced NLRP3 inflammasome activation in the liverof mice [77] They found that SFN decreased the expression
of ASC caspase-1 and IL-1120573 levels additionally it inhibitedthe activity of caspase-1 enzyme in primary hepatocytes Itwas also shown that SFN reduced the palmitate-inducedROS production by the mitochondria implying that SFNprevented mitochondrial dysfunction and this protectingmechanism was in part mediated by the activation of AMPKThey concluded that activation of AMPK and autophagy bySFN could protect from mitochondrial dysfunction inducedby saturated fatty acids resulting in a downregulation of fat-induced activation of the NLRP3 inflammasome
5 NLRP3 Inflammasome and theXenohormesis Hypothesis
As it was described in detail above polyphenols like resvera-trol curcumin EGCG and quercetin are potent inhibitors ofNLRP3 inflammasome-mediated IL-1120573 production typicallyacting at more than one element of the involved pathways(Figure 3)However it should be noted that these polyphenolshave an evenmuch broader biological effect as they influencea variety of pathways [119] though not all are directlyconnected to the function of the NLRP3 inflammasomeImportantly more than 8000 natural polyphenols have beendescribed [120] providing a large library of compounds aspotential inflammasome inhibitors Many of these polyphe-nols (such as resveratrol and curcumin) are overproducedby stressed plants triggering pathways mimicking the effectof caloric restriction It has been proposed that organismsfrom yeast to humans consuming stressed plants couldinterpret the stress signal carried by such polyphenols as apotential risk of future limitation of food availability and in
12 Mediators of Inflammation
turn adapting for the pursuit of longevity a theory termedas Xenohormesis [121ndash123] Interestingly the structurallyunrelated resveratrol and curcumin can achieve this caloricrestriction mimicking effect by activating AMPK and Sirt1[124] However polyphenols are also known to have anantioxidant effect activate glutathione S-transferases andinhibit COX enzymes among many other effects [125 126]Interestingly one of the most frequently used COX inhibitoris aspirin a derivative of another stress-induced phytochem-ical salicylic acid
A major concern of polyphenol use in therapy is thebioavailability of these compounds Nevertheless typicaldietary polyphenol intake is about 14mgkgday which iswithin the range of providing biologically active doses [127]
6 Concluding Remarks
Most of the time inflammasome-mediated IL-1120573 productionor caspase-mediated pyroptosis is beneficial for the host as itprotects from infection or prevents further damageHoweverprolonged cytokine production as in the case of sterileinflammation caused by endogenous danger signals maylead to the development of autoinflammatory or metabolicdiseases Chronic inflammation compromises the hostrsquos lifequality and requires sustained pharmacological and surgicaltreatments The paradigm of drug discovery in Westernmedicine is to develop highly selective compounds againstindividual druggable targets Currently the main treatmentmethods for these patients are targeting IL-1120573 Howeverprolonged usage of drugs may induce different side effectsfurthermore some form of medications are very expensivewhich limits their widespread use
Besides the high expenses another drawback of tradi-tional drug design is that many of the promising compoundsfail in the early or later stages of drug development Tradi-tional medicine uses many plant products to treat diseaseshowever the exact mechanisms behind their use is stillmostly lacking partially as a consequence of the pleiotropiceffect of the active compounds as detailed in this reviewNevertheless clarification of the molecular mechanism ofaction of such natural compounds already used in traditionalmedicine for quite some time will undoubtedly aid in theproduction of safe and cheap candidate medications to beused in the treatment of diseases including those appearingas a consequence of NLRP3 inflammasome-mediated IL-1120573overproduction
Competing Interests
The authors declare no conflict of interests
Acknowledgments
This work was supported by OTKA-K 109429 Szilvia Benkois a receiver of Lajos Szodoray Postdoctoral Fellowship andJanos Bolyai Postdoctoral Fellowship
References
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[2] G Meng F Zhang I Fuss A Kitani and W Strober ldquoA muta-tion in the Nlrp3 gene causing inflammasome hyperactivationpotentiates Th17 cell-dominant immune responsesrdquo Immunityvol 30 no 6 pp 860ndash874 2009
[3] D Lasiglie E Traggiai S Federici et al ldquoRole of IL-1 beta in thedevelopment of human TH17 cells lesson fromNLPR3mutatedpatientsrdquo PLoS ONE vol 6 no 5 Article ID e20014 2011
[4] H Schneider F Pitossi D Balschun A Wagner A Del Reyand H O Besedovsky ldquoA neuromodulatory role of interleukin-1120573 in the hippocampusrdquo Proceedings of the National Academy ofSciences of the United States of America vol 95 no 13 pp 7778ndash7783 1998
[5] E Gabay G Wolf Y Shavit R Yirmiya and M Tal ldquoChronicblockade of interleukin-1 (IL-1) prevents and attenuates neuro-pathic pain behavior and spontaneous ectopic neuronal activityfollowing nerve injuryrdquo European Journal of Pain vol 15 no 3pp 242ndash248 2011
[6] A del Rey A V Apkarian M Martina and H O BesedovskyldquoChronic neuropathic pain-like behavior and brain-borne IL-1120573rdquo Annals of the New York Academy of Sciences vol 1262 no 1pp 101ndash107 2012
[7] R Yirmiya and I Goshen ldquoImmune modulation of learningmemory neural plasticity and neurogenesisrdquo Brain Behaviorand Immunity vol 25 no 2 pp 181ndash213 2011
[8] M R de Zoete N W Palm S Zhu and R A FlavellldquoInflammasomesrdquo Cold Spring Harbor Perspectives in Biologyvol 6 no 12 Article ID a016287 2014
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[11] S Mariathasan D S Weiss K Newton et al ldquoCryopyrinactivates the inflammasome in response to toxins and ATPrdquoNature vol 440 no 7081 pp 228ndash232 2006
[12] A G Hise J Tomalka S Ganesan et al ldquoAn essential role forthe NLRP3 inflammasome in host defense against the humanfungal pathogen candida albicansrdquo Cell Host and Microbe vol5 no 5 pp 487ndash497 2009
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[14] F Martinon V Petrilli A Mayor A Tardivel and J TschoppldquoGout-associated uric acid crystals activate the NALP3 inflam-masomerdquo Nature vol 440 no 7081 pp 237ndash241 2006
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Mediators of Inflammation 13
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[34] G M Tannahill and L A J OrsquoNeill ldquoThe emerging role ofmetabolic regulation in the functioning of Toll-like receptorsand the NOD-like receptor Nlrp3rdquo FEBS Letters vol 585 no11 pp 1568ndash1572 2011
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[36] F Bauernfeind E Bartok A Rieger L Franchi G Nunez andV Hornung ldquoCutting edge reactive oxygen species inhibitorsblock priming but not activation of the NLRP3 inflamma-somerdquo The Journal of Immunology vol 187 no 2 pp 613ndash6172011
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[42] V Hornung F Bauernfeind A Halle et al ldquoSilica crystals andaluminum salts activate the NALP3 inflammasome throughphagosomal destabilizationrdquo Nature Immunology vol 9 no 8pp 847ndash856 2008
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[45] X Wang W Jiang Y Yan et al ldquoRNA viruses promoteactivation of the NLRP3 inflammasome through a RIP1-RIP3-DRP1 signaling pathwayrdquoNature Immunology vol 15 no 12 pp1126ndash1133 2014
[46] T Ichinohe T Yamazaki T Koshiba and Y Yanagi ldquoMitochon-drial protein mitofusin 2 is required for NLRP3 inflammasomeactivation afterRNAvirus infectionrdquoProceedings of theNationalAcademy of Sciences of the United States of America vol 110 no44 pp 17963ndash17968 2013
[47] N Subramanian K Natarajan M R Clatworthy Z Wangand R N Germain ldquoThe adaptor MAVS promotes NLRP3mitochondrial localization and inflammasome activationrdquo Cellvol 153 no 2 pp 348ndash361 2013
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14 Mediators of Inflammation
moleculesrdquo ACS Chemical Biology vol 8 no 12 pp 2724ndash27332013
[49] K Nakahira J A Haspel V A K Rathinam et al ldquoAutophagyproteins regulate innate immune responses by inhibiting therelease of mitochondrial DNA mediated by the NALP3 inflam-masomerdquo Nature Immunology vol 12 no 3 pp 222ndash230 2011
[50] T Misawa M Takahama T Kozaki et al ldquoMicrotubule-drivenspatial arrangement ofmitochondria promotes activation of theNLRP3 inflammasomerdquo Nature Immunology vol 14 no 5 pp454ndash460 2013
[51] M M Budai A Varga S Milesz J Tozser and S BenkoldquoAloe vera downregulates LPS-induced inflammatory cytokineproduction and expression of NLRP3 inflammasome in humanmacrophagesrdquo Molecular Immunology vol 56 no 4 pp 471ndash479 2013
[52] J-W Han D-W Shim W-Y Shin et al ldquoAnti-inflammatoryeffect of emodin via attenuation of NLRP3 inflammasomeactivationrdquo International Journal of Molecular Sciences vol 16no 4 pp 8102ndash8109 2015
[53] Y Li J Li S Li et al ldquoCurcumin attenuates glutamate neurotox-icity in the hippocampus by suppression of ER stress-associatedTXNIPNLRP3 inflammasome activation in a manner depen-dent onAMPKrdquoToxicology andApplied Pharmacology vol 286no 1 pp 53ndash63 2015
[54] Z Gong J Zhou H Li et al ldquoCurcumin suppresses NLRP3inflammasome activation and protects against LPS-inducedseptic shockrdquo Molecular Nutrition and Food Research vol 59no 11 pp 2132ndash2142 2015
[55] P-Y Tsai S-M Ka J-M Chang et al ldquoEpigallocatechin-3-gallate prevents lupus nephritis development in mice viaenhancing the Nrf2 antioxidant pathway and inhibiting NLRP3inflammasome activationrdquo Free Radical Biology and Medicinevol 51 no 3 pp 744ndash754 2011
[56] Z Gao Y Han Y Hu et al ldquoTargeting HO-1 byepigallocatechin-3-gallate reduces contrast-induced renalinjury via anti-oxidative stress and anti-inflammationpathwaysrdquo PLOS ONE vol 11 no 2 article e0149032 2016
[57] V Rajanbabu L Galam J Fukumoto et al ldquoGenipin suppressesNLRP3 inflammasome activation through uncoupling protein-2rdquo Cellular Immunology vol 297 no 1 pp 40ndash45 2015
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[62] C-W Pan Z-Z Pan J-J Hu et al ldquoMangiferin alleviateslipopolysaccharide and D-galactosamine-induced acute liverinjury by activating the Nrf2 pathway and inhibiting NLRP3inflammasome activationrdquo European Journal of Pharmacologyvol 770 pp 85ndash91 2016
[63] J I Hori D S Zamboni D B Carrao GHGoldman andAABerretta ldquoThe inhibition of inflammasome by Brazilian propo-lis (EPP-AF)rdquo Evidence-Based Complementary and AlternativeMedicine vol 2013 Article ID 418508 11 pages 2013
[64] C Wang Y Pan Q-Y Zhang F-M Wang and L-D KongldquoQuercetin and allopurinol ameliorate kidney injury in STZ-treated rats with regulation of renal NLRP3 inflammasomeactivation and lipid accumulationrdquo PLoS ONE vol 7 no 6Article ID e38285 2012
[65] Q-H Hu X Zhang Y Pan Y-C Li and L-D Kong ldquoAllop-urinol quercetin and rutin ameliorate renal NLRP3 inflamma-some activation and lipid accumulation in fructose-fed ratsrdquoBiochemical Pharmacology vol 84 no 1 pp 113ndash125 2012
[66] WWangCWangX-QDing et al ldquoQuercetin and allopurinolreduce liver thioredoxin-interacting protein to alleviate inflam-mation and lipid accumulation in diabetic ratsrdquo British Journalof Pharmacology vol 169 no 6 pp 1352ndash1371 2013
[67] Q-Y Zhang Y Pan R Wang et al ldquoQuercetin inhibitsAMPKTXNIP activation and reduces inflammatory lesions toimprove insulin signaling defect in the hypothalamus of highfructose-fed ratsrdquo Journal of Nutritional Biochemistry vol 25no 4 pp 420ndash428 2014
[68] J Wu X Xu Y Li et al ldquoQuercetin luteolin and epigallo-catechin gallate alleviate TXNIP and NLRP3-mediated inflam-mation and apoptosis with regulation of AMPK in endothelialcellsrdquo European Journal of Pharmacology vol 745 pp 59ndash682015
[69] W Jiang Y Huang N Han et al ldquoQuercetin suppresses NLRP3inflammasome activation and attenuates histopathology in a ratmodel of spinal cord injuryrdquo Spinal Cord vol 54 pp 592ndash5962016
[70] Y Fu Y Wang L Du et al ldquoResveratrol inhibits ionisingirradiation-induced inflammation in MSCs by activating Sirt1and limiting NLRP-3 inflammasome activationrdquo InternationalJournal ofMolecular Sciences vol 14 no 7 pp 14105ndash14118 2013
[71] T-T Huang H-C Lai Y-B Chen et al ldquoCis-Resveratrolproduces anti-inflammatory effects by inhibiting canonicaland non-canonical inflammasomes in macrophagesrdquo InnateImmunity vol 20 no 7 pp 735ndash750 2014
[72] Y-P Chang S-M Ka W-H Hsu et al ldquoResveratrol inhibitsNLRP3 inflammasome activation by preserving mitochondrialintegrity and augmenting autophagyrdquo Journal of Cellular Physi-ology vol 230 no 7 pp 1567ndash1579 2015
[73] S J Yang and Y Lim ldquoResveratrol ameliorates hepaticmetaflammation and inhibits NLRP3 inflammasome activa-tionrdquoMetabolism vol 63 no 5 pp 693ndash701 2014
[74] D-M Sui Q Xie W-J Yi et al ldquoResveratrol protects againstsepsis-associated encephalopathy and inhibits the NLRP3IL-1 120573 axis in microgliardquo Mediators of Inflammation vol 2016Article ID 1045657 10 pages 2016
[75] J Wu X Li G Zhu Y Zhang M He and J Zhang ldquoTherole of Resveratrol-inducedmitophagyautophagy in peritonealmesothelial cells inflammatory injury via NLRP3 inflamma-some activation triggered bymitochondrial ROSrdquoExperimentalCell Research vol 341 no 1 pp 42ndash53 2016
[76] Y W An K A Jhang S Y Woo J L Kang and Y HChong ldquoSulforaphane exerts its anti-inflammatory effectagainst amyloid-120573 peptide via STAT-1 dephosphorylationand activation of Nrf2HO-1 cascade in human THP-1macrophagesrdquo Neurobiology of Aging vol 38 pp 1ndash10 2016
[77] G Yang H E Lee and J Y Lee ldquoA pharmacological inhibitorof NLRP3 inflammasome prevents non-alcoholic fatty liver
Mediators of Inflammation 15
disease in a mouse model induced by high fat dietrdquo ScientificReports vol 6 Article ID 24399 2016
[78] L Franchi R Munoz-Planillo and G Nunez ldquoSensing andreacting to microbes through the inflammasomesrdquo NatureImmunology vol 13 no 4 pp 325ndash332 2012
[79] S L Cassel and F S Sutterwala ldquoSterile inflammatory responsesmediated by the NLRP3 inflammasomerdquo European Journal ofImmunology vol 40 no 3 pp 607ndash611 2010
[80] M-S Tan J-T Yu T Jiang X-C Zhu and L Tan ldquoThe NLRP3inflammasome in alzheimerrsquos diseaserdquoMolecular Neurobiologyvol 48 no 3 pp 875ndash882 2013
[81] M Gold and J El Khoury ldquo120573-amyloid microglia andthe inflammasome in Alzheimerrsquos diseaserdquo Seminars inImmunopathology vol 37 no 6 pp 607ndash611 2015
[82] P M Peeters T N Perkins E F M Wouters B T Mossmanand N L Reynaert ldquoSilica induces NLRP3 inflammasomeactivation in human lung epithelial cellsrdquo Particle and FibreToxicology vol 10 no 1 article 3 2013
[83] H Watanabe O Gaide V Petrilli et al ldquoActivation of the IL-1120573-processing inflammasome is involved in contact hypersen-sitivityrdquo Journal of Investigative Dermatology vol 127 no 8 pp1956ndash1963 2007
[84] X Dai K Sayama M Tohyama et al ldquoMite allergen is adanger signal for the skin via activation of inflammasome inkeratinocytesrdquo Journal of Allergy and Clinical Immunology vol127 no 3 pp 806ndash814 2011
[85] A Varga M M Budai S Milesz A Bacsi J Tozser and SBenko ldquoRagweed pollen extract intensifies lipopolysaccharide-induced priming of NLRP3 inflammasome in humanmacrophagesrdquo Immunology vol 138 no 4 pp 392ndash4012013
[86] B Vandanmagsar Y-H Youm A Ravussin et al ldquoThe NLRP3inflammasome instigates obesity-induced inflammation andinsulin resistancerdquo Nature Medicine vol 17 no 2 pp 179ndash1892011
[87] H Wen D Gris Y Lei et al ldquoFatty acid-induced NLRP3-ASCinflammasome activation interferes with insulin signalingrdquoNature Immunology vol 12 no 5 pp 408ndash415 2011
[88] L Liang X Tan Q Zhou et al ldquoIL-1120573 triggered by pepti-doglycan and lipopolysaccharide through TLR24 and ROS-NLRP3 inflammasome- dependent pathways is involved inocular behcetrsquos diseaserdquo Investigative Ophthalmology and VisualScience vol 54 no 1 pp 402ndash414 2013
[89] S Rosengren H M Hoffman W Bugbee and D L BoyleldquoExpression and regulation of cryopyrin and related proteinsin rheumatoid arthritis synoviumrdquo Annals of the RheumaticDiseases vol 64 no 5 pp 708ndash714 2005
[90] J M Kahlenberg ldquoAnti-inflammatory panaceaThe expandingtherapeutics of interleukin-1 blockaderdquo Current Opinion inRheumatology vol 28 no 3 pp 197ndash203 2016
[91] C-H Chien M-J Lee H-C Liou H-H Liou and W-MFu ldquoLocal immunosuppressive microenvironment enhancesmigration of melanoma cells to lungs in DJ-1 knockout micerdquoPLoS ONE vol 10 no 2 Article ID e0115827 2015
[92] C Antonopoulos and G R Dubyak ldquoChemotherapy engagesmultiple pathways leading to IL-1120573 production by myeloidleukocytesrdquo OncoImmunology vol 3 no 1 Article ID e274992014
[93] E Ozaki M Campbell and S L Doyle ldquoTargeting the NLRP3inflammasome in chronic inflammatory diseases current per-spectivesrdquo Journal of Inflammation Research vol 8 pp 15ndash272015
[94] J H Hamman ldquoComposition and applications of Aloe vera leafgelrdquoMolecules vol 13 no 8 pp 1599ndash1616 2008
[95] L Langmead R J Makins and D S Rampton ldquoAnti-inflammatory effects of aloe vera gel in human colorectalmucosa in vitrordquo Alimentary Pharmacology and Therapeuticsvol 19 no 5 pp 521ndash527 2004
[96] N Yun C-H Lee and S-M Lee ldquoProtective effect of Aloe veraon polymicrobial sepsis inmicerdquo Food andChemical Toxicologyvol 47 no 6 pp 1341ndash1348 2009
[97] C S Yu F S Yu J K Chan et al ldquoAloe-emodin affects the levelsof cytokines and functions of leukocytes from Sprague-Dawleyratsrdquo In Vivo vol 20 no 4 pp 505ndash509 2006
[98] M Pulido-Moran J Moreno-Fernandez C Ramirez-Tortosaand M Ramirez-Tortosa ldquoCurcumin and healthrdquo Moleculesvol 21 no 3 article E264 2016
[99] Y-F Dong L-X Wang X Huang et al ldquoKir61 knock-down aggravates cerebral ischemiareperfusion-induced neuralinjury in micerdquo CNS Neuroscience and Therapeutics vol 19 no8 pp 617ndash624 2013
[100] P J Maier K Zemoura M A Acuna G E Yevenes HU Zeilhofer and D Benke ldquoIschemia-like oxygen and glu-cose deprivation mediates down-regulation of cell surface 120574-aminobutyric acidB receptors via the endoplasmic reticulum(ER) stress-induced transcription factor CCAATenhancer-binding protein (CEBP)-homologous protein (CHOP)rdquo TheJournal of Biological Chemistry vol 289 no 18 pp 12896ndash129072014
[101] H-Y Shin S-H Kim H-J Jeong et al ldquoEpigallocatechin-3-gallate inhibits secretion of TNF-120572 IL-6 and IL-8 through theattenuation of ERK and NF-120581B in HMC-1 cellsrdquo InternationalArchives of Allergy and Immunology vol 142 no 4 pp 335ndash3442007
[102] W P Pulskens L M Butter G J Teske et al ldquoNlrp3 preventsearly renal interstitial edema and vascular permeability inunilateral ureteral obstructionrdquo PLoS ONE vol 9 no 1 ArticleID e85775 2014
[103] S Kamath and C A Roobottom ldquoHyperdense pericardial effu-sion in dermatomyositis and contrast induced nephropathyrdquoEmergency Radiology vol 11 no 3 pp 177ndash179 2005
[104] T Akao K Kobashi and M Aburada ldquoEnzymic studies onthe animal and intestinal bacterial metabolism of geniposiderdquoBiological and Pharmaceutical Bulletin vol 17 no 12 pp 1573ndash1576 1994
[105] R Wang K C MoYung M H Zhang and K Poon ldquoUCP2-and non-UCP2-mediated electric current in eukaryotic cellsexhibits different propertiesrdquo Environmental Science and Pollu-tion Research vol 22 no 24 pp 19618ndash19631 2015
[106] J-M Lu Q Yao and C Chen ldquoGinseng compounds an updateon their molecular mechanisms and medical applicationsrdquoCurrent Vascular Pharmacology vol 7 no 3 pp 293ndash302 2009
[107] E Hernandez-Cuellar K Tsuchiya H Hara et al ldquoCuttingedge nitric oxide inhibits the NLRP3 inflammasomerdquo TheJournal of Immunology vol 189 no 11 pp 5113ndash5117 2012
[108] B B Mishra V A K Rathinam G W Martens et alldquoNitric oxide controls the immunopathology of tuberculosis byinhibiting NLRP3 inflammasome-dependent processing of IL-1120573rdquo Nature Immunology vol 14 no 1 pp 52ndash60 2013
[109] T Matsuno S-K Jung Y Matsumoto M Saito and JMorikawa ldquoPreferential cytotoxicity to tumor cells of 35-diprenyl-4-hydroxycinnamic acid (artepillin C) isolated frompropolisrdquo Anticancer Research vol 17 no 5A pp 3565ndash35681997
16 Mediators of Inflammation
[110] X Zhang J-H Zhang X-Y Chen et al ldquoReactive oxy-gen species-induced TXNIP drives fructose-mediated hepaticinflammation and lipid accumulation through NLRP3 inflam-masome activationrdquo Antioxidants and Redox Signaling vol 22no 10 pp 848ndash870 2015
[111] A Zendedel S Johann S Mehrabi et al ldquoActivation and reg-ulation of NLRP3 inflammasome by intrathecal application ofSDF-1a in a spinal cord injury modelrdquoMolecular Neurobiologyvol 53 no 5 pp 3063ndash3075 2016
[112] H Inoue and R Nakata ldquoResveratrol targets in inflammationrdquoEndocrineMetabolic and ImmuneDisordersmdashDrug Targets vol15 no 3 pp 186ndash195 2015
[113] S S Kulkarni and C Canto ldquoThe molecular targets of resver-atrolrdquo Biochimica et Biophysica Acta (BBA)mdashMolecular Basis ofDisease vol 1852 no 6 pp 1114ndash1123 2015
[114] C A Houghton R G Fassett and J S Coombes ldquoSul-foraphane translational research from laboratory bench toclinicrdquo Nutrition Reviews vol 71 no 11 pp 709ndash726 2013
[115] A T Dinkova-Kostova W D Holtzclaw R N Cole et alldquoDirect evidence that sulfhydryl groups of Keap1 are the sensorsregulating induction of phase 2 enzymes that protect againstcarcinogens and oxidantsrdquo Proceedings of the National Academyof Sciences of the United States of America vol 99 no 18 pp11908ndash11913 2002
[116] E Heiss C Herhaus K Klimo H Bartsch and C GerhauserldquoNuclear factor 120581B is a molecular target for sulforaphane-mediated anti-inflammatory mechanismsrdquo The Journal of Bio-logical Chemistry vol 276 no 34 pp 32008ndash32015 2001
[117] A Alfieri S Srivastava R C M Siow et al ldquoSulforaphanepreconditioning of the Nrf2HO-1 defense pathway protectsthe cerebral vasculature against blood-brain barrier disruptionand neurological deficits in strokerdquo Free Radical Biology andMedicine vol 65 pp 1012ndash1022 2013
[118] C Lee G H Park S-R Lee and J-H Jang ldquoAttenuation of120573 -amyloid-induced oxidative cell death by sulforaphane viaactivation of NF-E2-related factor 2rdquo Oxidative Medicine andCellular Longevity vol 2013 Article ID 313510 12 pages 2013
[119] E Barrajon-Catalan M Herranz-Lopez J Joven et al ldquoMolec-ular promiscuity of plant polyphenols in the management ofage-related diseases far beyond their antioxidant propertiesrdquoAdvances in Experimental Medicine and Biology vol 824 pp141ndash159 2014
[120] L Bravo ldquoPolyphenols chemistry dietary sources metabolismand nutritional significancerdquo Nutrition Reviews vol 56 no 11pp 317ndash333 1998
[121] D W Lamming J G Wood and D A Sinclair ldquoSmallmolecules that regulate lifespan evidence for xenohormesisrdquoMolecular Microbiology vol 53 no 4 pp 1003ndash1009 2004
[122] K T Howitz and D A Sinclair ldquoXenohormesis sensing thechemical cues of other speciesrdquo Cell vol 133 no 3 pp 387ndash3912008
[123] P L Hooper P L Hooper M Tytell and L Vıgh ldquoXeno-hormesis health benefits from an eon of plant stress responseevolutionrdquoCell Stress and Chaperones vol 15 no 6 pp 761ndash7702010
[124] B L Queen and T O Tollefsbol ldquoPolyphenols and agingrdquoCurrent Aging Science vol 3 no 1 pp 34ndash42 2010
[125] J A Baur and D A Sinclair ldquoTherapeutic potential of resvera-trol the in vivo evidencerdquo Nature Reviews Drug Discovery vol5 no 6 pp 493ndash506 2006
[126] R A Sharma A J Gescher and W P Steward ldquoCurcumin thestory so farrdquoEuropean Journal of Cancer vol 41 no 13 pp 1955ndash1968 2005
[127] K Milton ldquoMicronutrient intakes of wild primates are humansdifferentrdquo Comparative Biochemistry and Physiology Part AMolecular amp Integrative Physiology vol 136 no 1 pp 47ndash592003
ROS release upon the NLRP3 activator nigericin treatment Itwas also suggested that artepillin C significantly contributedto the modulation of chemokine-mediated inflammation asit significantly downregulated the release of IL-1120573 IL-12p40and TNF120572 by LPS + IFN120574-treated RAW2647 cells whereasthe synthesis of IL-1120572 and IL-6 was not affected Besidesnigericin-mediated IL-1120573 production propolis also inhibitedLegionella pneumophila-induced IL-1120573 cytokine secretionin LPS-primed BMDMs This indicates that both NLRP3and NLRC4 inflammasome functions may be regulated bypropolis however further studies are required to clarify thedetailed molecular mechanism of the observed results
48 Quercetin Quercetin a kind of flavonoid found in avariety of vegetables beverages fruits and herbs exhibitsanti-inflammatory and antioxidant properties Quercetinwasreported to reduce inflammation in visceral adipose tissueprimary human adipocytes and the kidney of fructose-fedrats It was also shown to prevent diabetic kidney injury inratsHowever themechanisms of the action of quercetinwerenot clarified
It has been described that quercetin attenuated fructose-induced hyperuricemia and renal dysfunction In a studyusing streptozotocin- (STZ-) induced diabetic nephropa-thy rat model leading to hyperuricemia and dyslipidemiaquercetin was found to block NLRP3 inflammasome acti-vation [64] It was shown that the STZ-induced expres-sion of inflammasome components was restrained and IL-1120573 secretion was reduced by quercetin treatment Similarresults were obtained studying inflammatory responses infructose-induced hyperuricemia in rat [65] They showedthat fructose significantly elevated the expression of renalNLRP3 ASC and caspase-1 expression while quercetintreatment ameliorated the expression of these proteins Basedon their findings it was suggested that fructose-mediatedrenal NLRP3 inflammasome activation and proinflamma-tory cytokine overproduction may be associated with theimpaired cross talk between renal JAK2-STAT3 and PPAR-120572signaling pathway that in turn regulate renal inflammation
Furthermore it was shown that quercetin markedlyinhibited the overexpression of hepatic TXNIP in additionto reducing the production of ROS and the activation ofNLRP3 inflammasome consequently resulting in decreasedIL-1120573 secretion [66 110]They also showed that the decreasedcaspase-1 activity downregulated the caspase-1-dependentactivation of SREBPs that are involved in fatty acid andcholesterol synthesis They suggested that regulation of theTXNIP-NLRP3-SREBPs pathway by quercetin may partiallymediate the alleviation of hepatic steatosis in these diabeticrats
It was also shown that quercetin treatment regulatedAMPK pathway activation glutamine-glutamate cycle dys-function and TXNIP overexpression moreover it sup-pressed NF120581B pathway eventually leading to impairedNLRP3 inflammasome activation and IL-1120573 production inthe hypothalamus of high fructose- (HF-) fed rats [67]
Using human umbilical vein endothelial cells anothergroup reported that quercetin suppressed palmitate- (PA-) induced IL-1120573 and IL-6 induction [68] Downregulation
of NLRP3 induction was probably partially mediated viathe inhibition of ROS production and TXNIP expressionquercetin also inhibited IKK120573 activation by attenuatingits phosphorylation Furthermore quercetin treatment pro-tected cells against PA insult and significantly reduced thenumber of apoptotic cells Moreover quercetin amelioratedER stress-induced endothelial dysfunction through the acti-vation of AMPK
NLRP3 inflammasome is also recognized to have animportant role in the spinal cord tissue after traumatic spinalcord injury (SCI) and targeting the NLRP3 inflammasomecan inhibit neuroinflammation thereby improving func-tional recovery in SCI rats [111]
Very recently in a ratmodel of SCI quercetin administra-tion was shown to significantly improve functional recovery[69] Histopathological changes of the spinal cord such ascongestion edema neutrophil infiltration and structuraldisruption were inhibited by quercetin administration Toformulate a molecular mechanism the authors showed thatquercetin administration significantly reduced inflammatorycytokine IL-1120573 IL-18 and TNF120572 levels it also reduced theNLRP3 ASC and active caspase-1 protein expression andROS production However further studies are needed tobetter characterize the mechanisms of action underlying thebeneficial effects of quercetin in inflammation and immunity
49 Resveratrol Resveratrol is a polyphenol present inthe skin of grapes and mulberry commonly used in redwine production The beneficial effects of resveratrol arethought to be mediated in part by its antioxidant andanti-inflammatory properties exhibiting beneficial effectsin several diseases [112] Resveratrol exists as two isomerscis- and trans-resveratrol The cis isomer is thought to beproduced naturally during grape fermentation as a resultof isomerization of the trans isomer by yeast isomerasesFurthermore cis-resveratrol can be obtained by exposure ofthe trans isomer to sunlight Several studies have shown thattrans-resveratrol exhibits a wide range of biological activitiesincluding anti-inflammatory antioxidant anticarcinogenicantiaging antiplatelet aggregation immune-modulatory andchemoprevention effects However only few studies havebeen performed to examine the biological effects of the cisisomer Studies on cis-resveratrol have demonstrated thatit also possesses anticancer antimicrobial and antiplateletaggregation activities
One of the biological roles of resveratrol is to initiate theactivation of sirtuin 1 (Sirt1) is a deacetylase that modifies andinactivates inflammatory genes At high doses resveratrolhas been shown to activate AMPK which is involved inthe negative regulation of the NLRP3-inflammasome [113]It was also shown that ionizing radiation-induced IL-1120573secretion by human mesenchymal stem cells (MSCs) aneffect that was effectively abrogated by pretreatment withresveratrol [70] Radiation-induced increase in IL-1120573 occursvia the NLRP3 inflammasome activation however resver-atrol treatment attenuated the expression of NLRP3 It wasalso demonstrated that resveratrol treatment upregulated theexpression of Sirt1 In conclusion it is suggested that Sirt1
10 Mediators of Inflammation
inhibits NF120581B transcriptional activity through deacetylationthat in turn limits the transcription of NLRP3
In another study it was shown that cis-resveratrol pre-treatment significantly inhibited IL-1120573 secretion in THP-1 cellculture supernatants interestingly cis-resveratrol inducedIL-18 secretion under these conditions [71] Accordingly cis-resveratrol significantly reduced IL-1120573 mRNA expressionin contrast cis-resveratrol used at the same concentra-tion increased IL-18 mRNA expression Furthermore cis-resveratrol increased the mRNA and protein levels of NLRP1and NLRP3 indicating that the inhibitory effect of cis-resveratrol on IL-1120573 secretion is not due to the down-regulation of NLRP1 NLRP3 or ASC expression Similarresults were obtained on LPS-primed J774A1 macrophageswhere resveratrol inhibited the ATP-induced IL-1120573 secretionhowever in this study the authors did not find changes in theexpression of NLRP3 [72] showing that the resveratrol didnot inhibit the priming signal of NLRP3
Huang et al suggested that the inhibitory effect of cis-resveratrol on IL-1120573 secretion may be due to the reducedexpression of purinergic receptor P2X7R and the ER stressmarker GRP78 which leads to suppression of ROS pro-duction and reduced caspase-1 and caspase-4 activation Itwas found that cis-resveratrol also inhibited cyclooxygenase-(COX-) 2 expression which may be responsible for theobserved decrease of PGE2 production Furthermore inhi-bition of pro-IL-1120573 and COX-2 expression may occur bydownregulating the activation of the p38 MAPK path-way [71] Importantly in contrast to these observationsincreased phosphorylation of p38 was detected in ATP-activated J774A1 macrophages by Chang et al while itdid not significantly increase the phosphorylation levelsof ERK12 and it reduced the phosphorylation levels ofJNK12 The levels of mtDNA release into the cytosol weresignificantly reduced by resveratrol indicating that therewas less mitochondrial injury in resveratrol-treated cells[72] Furthermore the authors also showed that resveratrolincreased cellular cAMP level in J774A1 macrophages whichacts as a negative regulator of inflammatory responses andinhibits NLRP3 inflammasome activation
The effect of resveratrol on NLRP3 inflammasome wasfurther proved by a study showing that four weeks ofresveratrol administration inhibited the expression of NLRP3inflammasome components IL-1 IL-6 and TNF120572 and inlivers of HF-fed mice [73] They also showed that theregulatory effects of resveratrol on NLRP3 inflammasomemay come about through the combined effects of Sirt1 andSirt6
In a recent study [50] it was found that resveratroltreatment successfully suppressed the maturation of bothIL-1120573 and caspase-1 in response to Pam3CSK4 a TLR12agonist plus various inducers (like nigericin ATP MSUand silica) of the NLRP3-inflammasome In mouse BMDMshowever it did not affect the production of IL-1120573 medi-ated by the NLRC4-inflammasome (flagellin) or the AIM2-inflammasome (dsDNA) On a mouse model of acute goutthey indicated that resveratrol reduced the amount of matureIL-1120573 and the subsequent recruitment of neutrophils intothe peritoneal cavities of mice after challenge with MSU
crystals These findings indicate that resveratrol suppressesthe activation of the NLRP3-inflammasome both in vitroand in vivo As a possible mechanism they showed thatresveratrol at a substantially higher dosage successfullysuppressed mitochondrial ROS production Furthermoreresveratrol treatment prevented the accumulation of acety-lated 120572-tubulin thusinhibiting the proximate localization ofASC and NLRP3 in macrophages
In a very recent publication [74] the authors showed thatresveratrol preventedATP-inducedNLRP3 activation and IL-1120573 production in the BV2 cell line and in septic mice as wellThey also found that resveratrol treatment reduced NLRP3and IL-1120573 expression in the hippocampus of the mice andthey suggested that the protecting effect of resveratrol wasmediated via the increased expression of Sirt1 in BV2 cells
Another recent publication found that glucose-basedperitoneal dialysis increased mitochondrial ROS productionand subsequent IL-1120573 secretion through NLRP3 inflamma-some in human peritoneal mesothelial cells (HPMC) Asa mechanism for its action they showed that resveratrolinduced mitophagyautophagy of the cells via AMPK activa-tion and protected cells fromROS-inducedNLRP3-mediatedinflammatory injury [75]
410 Sulforaphane Sulforaphane (SFN) is a natural com-pound present in cruciferous vegetables such as broccolicabbage Brussel sprouts mustard and radish ChemicallySFN is an isothiocyanate that is known to react withsulfhydryl groups and tomodify proteins at cysteine residuesSulforaphane is produced from the precursor glucoraphaninby the enzymatic activity of myrosinase when the cell wallsof the plant are damaged for example during chewingSFN has been known as a cytoprotective agent for cancerprevention or treatment and it also has an important rolein cardiovascular neurologic and other diseases (reviewedin [114]) SFN is a known inducer of the Nrf2 antioxidantpathway as it activates the Nrf2 transcription factor byreacting with cysteine residues of its repressor Keap1 [115]In addition it also inhibits NF120581B signaling [116]
It was shown that SFN inhibited IL-1120573 processing byNLRP1- NLRP3- NLRC4- and AIM2- inflammasome com-plexes in mouse BMDMs [28] It was also demonstratedthat SFN inhibits the inflammasome in an Nrf2-independentmanner as SFN-mediated inhibition of NLRP3- andNLRC4-dependent IL-1120573 processing and secretion was not reversedin Nrf2-knockout BMDMs When SFN was added directlyto the cell lysates it did not inhibit IL-1120573 processingdemonstrating that SFN does not directly inhibit the proteaseactivity of caspase-1 The authors found that SFN-mediatedinhibition of the inflammasomes is not affected by ROSmodulation and neither proteasome-dependent proteolysisnor de novo protein synthesis is required for SFN-mediatedinhibition of the inflammasomes In a peritonitis model ofacute gout SFN treatment significantly reducedMSU crystal-induced IL-1120573 production demonstrating that SFN inhibitsthe NLRP3 inflammasome function in vivo Nonethelessthe authors concluded that SFN inhibits multiple inflam-masomes in vitro and in vivo by a mechanism independent
Mediators of Inflammation 11
ERKp38
NLRP3
ASCNLRP3
Caspase-1ROS
ER stress
P2X7R ATP
Cathepsin B
TLR
ROS
mtDNA
Sirt2
AcAc
AcAc
AMPK
A
A AC
C
C
Nrf2E
E
UCP2Ge
Ge
Ge
Gi
TXNIPC
NOGi
P
Sirt1R
R
R
R
M
M
M
Q
QQ
SS
S
R
Cardio-lipin
Acetylated 120572-tubulin
Ca2+ influx
IL-1120573
Pro-IL-1120573
K+efflux
120572-Tubulin
Pro-IL-1120573
NF120581B
Figure 3 Molecular targets of natural compounds affecting NLRP3 inflammasome-mediated IL-1 production
of inflammasome priming and Nrf2 signaling however theexact molecular mechanism was not explored
As SFN is able to penetrate the blood-brain barrier[117] it gained a considerable attention as a candidatefor Alzheimerrsquos disease (AD) therapy SFN was shown toprotect the brain from A120573-induced oxidative cell death viaactivation of Nrf2 signaling cascade [118] As A120573 fibrilshave been shown to activate NLRP3 inflammasome thequestion arose whether SFN may regulate this mechanismIn a very recent study it was shown that SFN significantlydownregulated IL-1120573 production and NLRP3 expression inA1205731ndash42 peptide-stimulated human THP-1 cells macrophages[76] It was found that A1205731ndash42 peptide-induced STAT-1phosphorylation was significantly attenuated by SFN Theauthors showed that SFN inducedNrf2 nuclear translocationwhich was subsequently accompanied by an increase in HO-1 protein levels Furthermore A1205731ndash42 peptide-induced IL-1120573 production was diminished by siRNA-mediated knock-down of Nrf2 or HO-1 They also found that the increasedproinflammatory miRNA-146a level following A1205731ndash42 treat-ment was significantly attenuated by SFN whereas miRNA-125b and miRNA-155 levels were not changed These arespecific proinflammatory miRNAs that were reported to beincreased in both the extracellular fluid and cerebrospinalfluid of AD patients In conclusion SFN can suppress A1205731ndash42-induced caspase-1-dependent inflammasome activationpossibly through inhibiting STAT-1 phosphorylation andactivation of the Nrf2HO-1 signaling pathway
Also very recently another research group reported thatoral administrations of SFN suppressed the saturated fattyacid-induced NLRP3 inflammasome activation in the liverof mice [77] They found that SFN decreased the expression
of ASC caspase-1 and IL-1120573 levels additionally it inhibitedthe activity of caspase-1 enzyme in primary hepatocytes Itwas also shown that SFN reduced the palmitate-inducedROS production by the mitochondria implying that SFNprevented mitochondrial dysfunction and this protectingmechanism was in part mediated by the activation of AMPKThey concluded that activation of AMPK and autophagy bySFN could protect from mitochondrial dysfunction inducedby saturated fatty acids resulting in a downregulation of fat-induced activation of the NLRP3 inflammasome
5 NLRP3 Inflammasome and theXenohormesis Hypothesis
As it was described in detail above polyphenols like resvera-trol curcumin EGCG and quercetin are potent inhibitors ofNLRP3 inflammasome-mediated IL-1120573 production typicallyacting at more than one element of the involved pathways(Figure 3)However it should be noted that these polyphenolshave an evenmuch broader biological effect as they influencea variety of pathways [119] though not all are directlyconnected to the function of the NLRP3 inflammasomeImportantly more than 8000 natural polyphenols have beendescribed [120] providing a large library of compounds aspotential inflammasome inhibitors Many of these polyphe-nols (such as resveratrol and curcumin) are overproducedby stressed plants triggering pathways mimicking the effectof caloric restriction It has been proposed that organismsfrom yeast to humans consuming stressed plants couldinterpret the stress signal carried by such polyphenols as apotential risk of future limitation of food availability and in
12 Mediators of Inflammation
turn adapting for the pursuit of longevity a theory termedas Xenohormesis [121ndash123] Interestingly the structurallyunrelated resveratrol and curcumin can achieve this caloricrestriction mimicking effect by activating AMPK and Sirt1[124] However polyphenols are also known to have anantioxidant effect activate glutathione S-transferases andinhibit COX enzymes among many other effects [125 126]Interestingly one of the most frequently used COX inhibitoris aspirin a derivative of another stress-induced phytochem-ical salicylic acid
A major concern of polyphenol use in therapy is thebioavailability of these compounds Nevertheless typicaldietary polyphenol intake is about 14mgkgday which iswithin the range of providing biologically active doses [127]
6 Concluding Remarks
Most of the time inflammasome-mediated IL-1120573 productionor caspase-mediated pyroptosis is beneficial for the host as itprotects from infection or prevents further damageHoweverprolonged cytokine production as in the case of sterileinflammation caused by endogenous danger signals maylead to the development of autoinflammatory or metabolicdiseases Chronic inflammation compromises the hostrsquos lifequality and requires sustained pharmacological and surgicaltreatments The paradigm of drug discovery in Westernmedicine is to develop highly selective compounds againstindividual druggable targets Currently the main treatmentmethods for these patients are targeting IL-1120573 Howeverprolonged usage of drugs may induce different side effectsfurthermore some form of medications are very expensivewhich limits their widespread use
Besides the high expenses another drawback of tradi-tional drug design is that many of the promising compoundsfail in the early or later stages of drug development Tradi-tional medicine uses many plant products to treat diseaseshowever the exact mechanisms behind their use is stillmostly lacking partially as a consequence of the pleiotropiceffect of the active compounds as detailed in this reviewNevertheless clarification of the molecular mechanism ofaction of such natural compounds already used in traditionalmedicine for quite some time will undoubtedly aid in theproduction of safe and cheap candidate medications to beused in the treatment of diseases including those appearingas a consequence of NLRP3 inflammasome-mediated IL-1120573overproduction
Competing Interests
The authors declare no conflict of interests
Acknowledgments
This work was supported by OTKA-K 109429 Szilvia Benkois a receiver of Lajos Szodoray Postdoctoral Fellowship andJanos Bolyai Postdoctoral Fellowship
References
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[2] G Meng F Zhang I Fuss A Kitani and W Strober ldquoA muta-tion in the Nlrp3 gene causing inflammasome hyperactivationpotentiates Th17 cell-dominant immune responsesrdquo Immunityvol 30 no 6 pp 860ndash874 2009
[3] D Lasiglie E Traggiai S Federici et al ldquoRole of IL-1 beta in thedevelopment of human TH17 cells lesson fromNLPR3mutatedpatientsrdquo PLoS ONE vol 6 no 5 Article ID e20014 2011
[4] H Schneider F Pitossi D Balschun A Wagner A Del Reyand H O Besedovsky ldquoA neuromodulatory role of interleukin-1120573 in the hippocampusrdquo Proceedings of the National Academy ofSciences of the United States of America vol 95 no 13 pp 7778ndash7783 1998
[5] E Gabay G Wolf Y Shavit R Yirmiya and M Tal ldquoChronicblockade of interleukin-1 (IL-1) prevents and attenuates neuro-pathic pain behavior and spontaneous ectopic neuronal activityfollowing nerve injuryrdquo European Journal of Pain vol 15 no 3pp 242ndash248 2011
[6] A del Rey A V Apkarian M Martina and H O BesedovskyldquoChronic neuropathic pain-like behavior and brain-borne IL-1120573rdquo Annals of the New York Academy of Sciences vol 1262 no 1pp 101ndash107 2012
[7] R Yirmiya and I Goshen ldquoImmune modulation of learningmemory neural plasticity and neurogenesisrdquo Brain Behaviorand Immunity vol 25 no 2 pp 181ndash213 2011
[8] M R de Zoete N W Palm S Zhu and R A FlavellldquoInflammasomesrdquo Cold Spring Harbor Perspectives in Biologyvol 6 no 12 Article ID a016287 2014
[9] M Dagenais A Skeldon and M Saleh ldquoThe inflammasomein memory of Dr Jurg Tschopprdquo Cell Death and Differentiationvol 19 no 1 pp 5ndash12 2012
[10] T-D Kanneganti N OzorenM Body-Malapel et al ldquoBacterialRNA and small antiviral compounds activate caspase-1 throughcryopyrinNalp3rdquoNature vol 440 no 7081 pp 233ndash236 2006
[11] S Mariathasan D S Weiss K Newton et al ldquoCryopyrinactivates the inflammasome in response to toxins and ATPrdquoNature vol 440 no 7081 pp 228ndash232 2006
[12] A G Hise J Tomalka S Ganesan et al ldquoAn essential role forthe NLRP3 inflammasome in host defense against the humanfungal pathogen candida albicansrdquo Cell Host and Microbe vol5 no 5 pp 487ndash497 2009
[13] M T Shio S C Eisenbarth M Savaria et al ldquoMalarialhemozoin activates theNLRP3 inflammasome through Lyn andSyk kinasesrdquo PLoS Pathogens vol 5 no 8 article e10005592009
[14] F Martinon V Petrilli A Mayor A Tardivel and J TschoppldquoGout-associated uric acid crystals activate the NALP3 inflam-masomerdquo Nature vol 440 no 7081 pp 237ndash241 2006
[15] J Tschopp and K Schroder ldquoNLRP3 inflammasome activationthe convergence of multiple signalling pathways on ROS pro-ductionrdquo Nature Reviews Immunology vol 10 no 3 pp 210ndash215 2010
[16] C Dostert V Petrilli R Van Bruggen C Steele B TMossmanand J Tschopp ldquoInnate immune activation through Nalp3inflammasome sensing of asbestos and silicardquo Science vol 320no 5876 pp 674ndash677 2008
Mediators of Inflammation 13
[17] A Halle V Hornung G C Petzold et al ldquoThe NALP3inflammasome is involved in the innate immune response toamyloid-120573rdquoNature Immunology vol 9 no 8 pp 857ndash865 2008
[18] B Pazar H-K Ea S Narayan et al ldquoBasic calcium phosphatecrystals induce monocytemacrophage IL-1120573 secretion throughthe NLRP3 inflammasome in vitrordquo Journal of Immunology vol186 no 4 pp 2495ndash2502 2011
[19] P Duewell H Kono K J Rayner et al ldquoNLRP3 inflammasomesare required for atherogenesis and activated by cholesterolcrystalsrdquo Nature vol 464 no 7293 pp 1357ndash1361 2010
[20] S Benko D J Philpott and S E Girardin ldquoThe microbial anddanger signals that activate Nod-like receptorsrdquo Cytokine vol43 no 3 pp 368ndash373 2008
[21] F G Bauernfeind G Horvath A Stutz et al ldquoCutting edgeNF-120581B activating pattern recognition and cytokine receptorslicense NLRP3 inflammasome activation by regulating NLRP3expressionrdquo Journal of Immunology vol 183 no 2 pp 787ndash7912009
[22] M G Ghonime O R Shamaa S Das et al ldquoInflammasomepriming by lipopolysaccharide is dependent upon ERK signal-ing and proteasome functionrdquo Journal of Immunology vol 192no 8 pp 3881ndash3888 2014
[23] Q He H You X-M Li T-H Liu P Wang and B-E WangldquoHMGB1 promotes the synthesis of pro-il-1120573 and pro-il-18by activation of p38 MAPK and NF-kB through receptorsfor advanced glycation end-products in macrophagesrdquo AsianPacific Journal of Cancer Prevention vol 13 no 4 pp 1365ndash13702012
[24] C Jin and R A Flavell ldquoMolecular mechanism of NLRP3inflammasome activationrdquo Journal of Clinical Immunology vol30 no 5 pp 628ndash631 2010
[25] S MMan and T-D Kanneganti ldquoRegulation of inflammasomeactivationrdquo Immunological Reviews vol 265 no 1 pp 6ndash212015
[26] K Shimada T R Crother J Karlin et al ldquoOxidized mito-chondrial DNA activates the NLRP3 inflammasome duringapoptosisrdquo Immunity vol 36 no 3 pp 401ndash414 2012
[27] G-S Lee N Subramanian A I Kim et al ldquoThe calcium-sensing receptor regulates the NLRP3 inflammasome throughCa2+ and cAMPrdquo Nature vol 491 no 7427 pp 123ndash127 2012
[28] A J Greaney SH Leppla andMMoayeri ldquoBacterial exotoxinsand the inflammasomerdquo Frontiers in Immunology vol 6 article570 2015
[29] E I Elliott and F S Sutterwala ldquoInitiation and perpetuation ofNLRP3 inflammasome activation and assemblyrdquo ImmunologicalReviews vol 265 no 1 pp 35ndash52 2015
[30] A Sokolovska C E Becker W K E Ip et al ldquoActiva-tion of caspase-1 by the NLRP3 inflammasome regulates theNADPHoxidaseNOX2 to control phagosome functionrdquoNatureImmunology vol 14 no 6 pp 543ndash553 2013
[31] S Kim Y Joe S O Jeong et al ldquoEndoplasmic reticulum stressis sufficient for the induction of IL-1120573 production via activationof the NF-120581B and inflammasome pathwaysrdquo Innate Immunityvol 20 no 8 pp 799ndash815 2014
[32] A G Lerner J-P Upton P V K Praveen et al ldquoIRE1120572induces thioredoxin-interacting protein to activate the NLRP3inflammasome and promote programmed cell death underirremediable ER stressrdquo Cell Metabolism vol 16 no 2 pp 250ndash264 2012
[33] S Freigang F Ampenberger G Spohn et al ldquoNrf2 is essentialfor cholesterol crystal-induced inflammasome activation and
exacerbation of atherosclerosisrdquo European Journal of Immunol-ogy vol 41 no 7 pp 2040ndash2051 2011
[34] G M Tannahill and L A J OrsquoNeill ldquoThe emerging role ofmetabolic regulation in the functioning of Toll-like receptorsand the NOD-like receptor Nlrp3rdquo FEBS Letters vol 585 no11 pp 1568ndash1572 2011
[35] M Haneklaus and L A J OrsquoNeill ldquoNLRP3 at the interfaceof metabolism and inflammationrdquo Immunological Reviews vol265 no 1 pp 53ndash62 2015
[36] F Bauernfeind E Bartok A Rieger L Franchi G Nunez andV Hornung ldquoCutting edge reactive oxygen species inhibitorsblock priming but not activation of the NLRP3 inflamma-somerdquo The Journal of Immunology vol 187 no 2 pp 613ndash6172011
[37] D Perregaux and C A Gabel ldquoInterleukin-1 beta maturationand release in response to ATP and nigericin Evidence thatpotassium depletion mediated by these agents is a necessaryand common feature of their activityrdquoThe Journal of BiologicalChemistry vol 269 no 21 pp 15195ndash15203 1994
[38] J M Kahlenberg K C Lundberg S B Kertesy Y Qu and GR Dubyak ldquoPotentiation of caspase-1 activation by the P2X7receptor is dependent on TLR signals and requires NF-120581B-driven protein synthesisrdquo Journal of Immunology vol 175 no11 pp 7611ndash7622 2005
[39] R Munoz-Planillo P Kuffa G Martınez-Colon B Smith TRajendiran and G Nunez ldquoK+ efflux is the common triggerof NLRP3 inflammasome activation by bacterial toxins andparticulate matterrdquo Immunity vol 38 no 6 pp 1142ndash1153 2013
[40] V Petrilli S Papin C Dostert A Mayor F Martinon and JTschopp ldquoActivation of the NALP3 inflammasome is triggeredby low intracellular potassium concentrationrdquo Cell Death andDifferentiation vol 14 no 9 pp 1583ndash1589 2007
[41] T Murakami J Ockinger J Yu et al ldquoCritical role for calciummobilization in activation of the NLRP3 inflammasomerdquo Pro-ceedings of the National Academy of Sciences of the United Statesof America vol 109 no 28 pp 11282ndash11287 2012
[42] V Hornung F Bauernfeind A Halle et al ldquoSilica crystals andaluminum salts activate the NALP3 inflammasome throughphagosomal destabilizationrdquo Nature Immunology vol 9 no 8pp 847ndash856 2008
[43] J Dan Dunn L A J Alvarez X Zhang and T SoldatildquoReactive oxygen species and mitochondria a nexus of cellularhomeostasisrdquo Redox Biology vol 6 pp 472ndash485 2015
[44] S S Iyer Q He J R Janczy et al ldquoMitochondrial cardiolipinis required for Nlrp3 inflammasome activationrdquo Immunity vol39 no 2 pp 311ndash323 2013
[45] X Wang W Jiang Y Yan et al ldquoRNA viruses promoteactivation of the NLRP3 inflammasome through a RIP1-RIP3-DRP1 signaling pathwayrdquoNature Immunology vol 15 no 12 pp1126ndash1133 2014
[46] T Ichinohe T Yamazaki T Koshiba and Y Yanagi ldquoMitochon-drial protein mitofusin 2 is required for NLRP3 inflammasomeactivation afterRNAvirus infectionrdquoProceedings of theNationalAcademy of Sciences of the United States of America vol 110 no44 pp 17963ndash17968 2013
[47] N Subramanian K Natarajan M R Clatworthy Z Wangand R N Germain ldquoThe adaptor MAVS promotes NLRP3mitochondrial localization and inflammasome activationrdquo Cellvol 153 no 2 pp 348ndash361 2013
[48] S Y Shaw K Tran A B Castoreno et al ldquoSelective modulationof autophagy innate immunity and adaptive immunity by small
14 Mediators of Inflammation
moleculesrdquo ACS Chemical Biology vol 8 no 12 pp 2724ndash27332013
[49] K Nakahira J A Haspel V A K Rathinam et al ldquoAutophagyproteins regulate innate immune responses by inhibiting therelease of mitochondrial DNA mediated by the NALP3 inflam-masomerdquo Nature Immunology vol 12 no 3 pp 222ndash230 2011
[50] T Misawa M Takahama T Kozaki et al ldquoMicrotubule-drivenspatial arrangement ofmitochondria promotes activation of theNLRP3 inflammasomerdquo Nature Immunology vol 14 no 5 pp454ndash460 2013
[51] M M Budai A Varga S Milesz J Tozser and S BenkoldquoAloe vera downregulates LPS-induced inflammatory cytokineproduction and expression of NLRP3 inflammasome in humanmacrophagesrdquo Molecular Immunology vol 56 no 4 pp 471ndash479 2013
[52] J-W Han D-W Shim W-Y Shin et al ldquoAnti-inflammatoryeffect of emodin via attenuation of NLRP3 inflammasomeactivationrdquo International Journal of Molecular Sciences vol 16no 4 pp 8102ndash8109 2015
[53] Y Li J Li S Li et al ldquoCurcumin attenuates glutamate neurotox-icity in the hippocampus by suppression of ER stress-associatedTXNIPNLRP3 inflammasome activation in a manner depen-dent onAMPKrdquoToxicology andApplied Pharmacology vol 286no 1 pp 53ndash63 2015
[54] Z Gong J Zhou H Li et al ldquoCurcumin suppresses NLRP3inflammasome activation and protects against LPS-inducedseptic shockrdquo Molecular Nutrition and Food Research vol 59no 11 pp 2132ndash2142 2015
[55] P-Y Tsai S-M Ka J-M Chang et al ldquoEpigallocatechin-3-gallate prevents lupus nephritis development in mice viaenhancing the Nrf2 antioxidant pathway and inhibiting NLRP3inflammasome activationrdquo Free Radical Biology and Medicinevol 51 no 3 pp 744ndash754 2011
[56] Z Gao Y Han Y Hu et al ldquoTargeting HO-1 byepigallocatechin-3-gallate reduces contrast-induced renalinjury via anti-oxidative stress and anti-inflammationpathwaysrdquo PLOS ONE vol 11 no 2 article e0149032 2016
[57] V Rajanbabu L Galam J Fukumoto et al ldquoGenipin suppressesNLRP3 inflammasome activation through uncoupling protein-2rdquo Cellular Immunology vol 297 no 1 pp 40ndash45 2015
[58] S-X Yu C-T DuW Chen et al ldquoGenipin inhibits NLRP3 andNLRC4 inflammasome activation via autophagy suppressionrdquoScientific Reports vol 5 article 17935 2015
[59] J Kim H Ahn B-C Han et al ldquoKorean red ginseng extractsinhibit NLRP3 and AIM2 inflammasome activationrdquo Immunol-ogy Letters vol 158 no 1-2 pp 143ndash150 2014
[60] S-J Yoon J-Y Park S Choi et al ldquoGinsenoside Rg3 regulatesS-nitrosylation of the NLRP3 inflammasome via suppression ofiNOSrdquo Biochemical and Biophysical Research Communicationsvol 463 no 4 pp 1184ndash1189 2015
[61] J Song J Li F Hou X Wang and B Liu ldquoMangiferininhibits endoplasmic reticulum stress-associated thioredoxin-interacting proteinNLRP3 inflammasome activation with reg-ulation of AMPK in endothelial cellsrdquo Metabolism vol 64 no3 pp 428ndash437 2015
[62] C-W Pan Z-Z Pan J-J Hu et al ldquoMangiferin alleviateslipopolysaccharide and D-galactosamine-induced acute liverinjury by activating the Nrf2 pathway and inhibiting NLRP3inflammasome activationrdquo European Journal of Pharmacologyvol 770 pp 85ndash91 2016
[63] J I Hori D S Zamboni D B Carrao GHGoldman andAABerretta ldquoThe inhibition of inflammasome by Brazilian propo-lis (EPP-AF)rdquo Evidence-Based Complementary and AlternativeMedicine vol 2013 Article ID 418508 11 pages 2013
[64] C Wang Y Pan Q-Y Zhang F-M Wang and L-D KongldquoQuercetin and allopurinol ameliorate kidney injury in STZ-treated rats with regulation of renal NLRP3 inflammasomeactivation and lipid accumulationrdquo PLoS ONE vol 7 no 6Article ID e38285 2012
[65] Q-H Hu X Zhang Y Pan Y-C Li and L-D Kong ldquoAllop-urinol quercetin and rutin ameliorate renal NLRP3 inflamma-some activation and lipid accumulation in fructose-fed ratsrdquoBiochemical Pharmacology vol 84 no 1 pp 113ndash125 2012
[66] WWangCWangX-QDing et al ldquoQuercetin and allopurinolreduce liver thioredoxin-interacting protein to alleviate inflam-mation and lipid accumulation in diabetic ratsrdquo British Journalof Pharmacology vol 169 no 6 pp 1352ndash1371 2013
[67] Q-Y Zhang Y Pan R Wang et al ldquoQuercetin inhibitsAMPKTXNIP activation and reduces inflammatory lesions toimprove insulin signaling defect in the hypothalamus of highfructose-fed ratsrdquo Journal of Nutritional Biochemistry vol 25no 4 pp 420ndash428 2014
[68] J Wu X Xu Y Li et al ldquoQuercetin luteolin and epigallo-catechin gallate alleviate TXNIP and NLRP3-mediated inflam-mation and apoptosis with regulation of AMPK in endothelialcellsrdquo European Journal of Pharmacology vol 745 pp 59ndash682015
[69] W Jiang Y Huang N Han et al ldquoQuercetin suppresses NLRP3inflammasome activation and attenuates histopathology in a ratmodel of spinal cord injuryrdquo Spinal Cord vol 54 pp 592ndash5962016
[70] Y Fu Y Wang L Du et al ldquoResveratrol inhibits ionisingirradiation-induced inflammation in MSCs by activating Sirt1and limiting NLRP-3 inflammasome activationrdquo InternationalJournal ofMolecular Sciences vol 14 no 7 pp 14105ndash14118 2013
[71] T-T Huang H-C Lai Y-B Chen et al ldquoCis-Resveratrolproduces anti-inflammatory effects by inhibiting canonicaland non-canonical inflammasomes in macrophagesrdquo InnateImmunity vol 20 no 7 pp 735ndash750 2014
[72] Y-P Chang S-M Ka W-H Hsu et al ldquoResveratrol inhibitsNLRP3 inflammasome activation by preserving mitochondrialintegrity and augmenting autophagyrdquo Journal of Cellular Physi-ology vol 230 no 7 pp 1567ndash1579 2015
[73] S J Yang and Y Lim ldquoResveratrol ameliorates hepaticmetaflammation and inhibits NLRP3 inflammasome activa-tionrdquoMetabolism vol 63 no 5 pp 693ndash701 2014
[74] D-M Sui Q Xie W-J Yi et al ldquoResveratrol protects againstsepsis-associated encephalopathy and inhibits the NLRP3IL-1 120573 axis in microgliardquo Mediators of Inflammation vol 2016Article ID 1045657 10 pages 2016
[75] J Wu X Li G Zhu Y Zhang M He and J Zhang ldquoTherole of Resveratrol-inducedmitophagyautophagy in peritonealmesothelial cells inflammatory injury via NLRP3 inflamma-some activation triggered bymitochondrial ROSrdquoExperimentalCell Research vol 341 no 1 pp 42ndash53 2016
[76] Y W An K A Jhang S Y Woo J L Kang and Y HChong ldquoSulforaphane exerts its anti-inflammatory effectagainst amyloid-120573 peptide via STAT-1 dephosphorylationand activation of Nrf2HO-1 cascade in human THP-1macrophagesrdquo Neurobiology of Aging vol 38 pp 1ndash10 2016
[77] G Yang H E Lee and J Y Lee ldquoA pharmacological inhibitorof NLRP3 inflammasome prevents non-alcoholic fatty liver
Mediators of Inflammation 15
disease in a mouse model induced by high fat dietrdquo ScientificReports vol 6 Article ID 24399 2016
[78] L Franchi R Munoz-Planillo and G Nunez ldquoSensing andreacting to microbes through the inflammasomesrdquo NatureImmunology vol 13 no 4 pp 325ndash332 2012
[79] S L Cassel and F S Sutterwala ldquoSterile inflammatory responsesmediated by the NLRP3 inflammasomerdquo European Journal ofImmunology vol 40 no 3 pp 607ndash611 2010
[80] M-S Tan J-T Yu T Jiang X-C Zhu and L Tan ldquoThe NLRP3inflammasome in alzheimerrsquos diseaserdquoMolecular Neurobiologyvol 48 no 3 pp 875ndash882 2013
[81] M Gold and J El Khoury ldquo120573-amyloid microglia andthe inflammasome in Alzheimerrsquos diseaserdquo Seminars inImmunopathology vol 37 no 6 pp 607ndash611 2015
[82] P M Peeters T N Perkins E F M Wouters B T Mossmanand N L Reynaert ldquoSilica induces NLRP3 inflammasomeactivation in human lung epithelial cellsrdquo Particle and FibreToxicology vol 10 no 1 article 3 2013
[83] H Watanabe O Gaide V Petrilli et al ldquoActivation of the IL-1120573-processing inflammasome is involved in contact hypersen-sitivityrdquo Journal of Investigative Dermatology vol 127 no 8 pp1956ndash1963 2007
[84] X Dai K Sayama M Tohyama et al ldquoMite allergen is adanger signal for the skin via activation of inflammasome inkeratinocytesrdquo Journal of Allergy and Clinical Immunology vol127 no 3 pp 806ndash814 2011
[85] A Varga M M Budai S Milesz A Bacsi J Tozser and SBenko ldquoRagweed pollen extract intensifies lipopolysaccharide-induced priming of NLRP3 inflammasome in humanmacrophagesrdquo Immunology vol 138 no 4 pp 392ndash4012013
[86] B Vandanmagsar Y-H Youm A Ravussin et al ldquoThe NLRP3inflammasome instigates obesity-induced inflammation andinsulin resistancerdquo Nature Medicine vol 17 no 2 pp 179ndash1892011
[87] H Wen D Gris Y Lei et al ldquoFatty acid-induced NLRP3-ASCinflammasome activation interferes with insulin signalingrdquoNature Immunology vol 12 no 5 pp 408ndash415 2011
[88] L Liang X Tan Q Zhou et al ldquoIL-1120573 triggered by pepti-doglycan and lipopolysaccharide through TLR24 and ROS-NLRP3 inflammasome- dependent pathways is involved inocular behcetrsquos diseaserdquo Investigative Ophthalmology and VisualScience vol 54 no 1 pp 402ndash414 2013
[89] S Rosengren H M Hoffman W Bugbee and D L BoyleldquoExpression and regulation of cryopyrin and related proteinsin rheumatoid arthritis synoviumrdquo Annals of the RheumaticDiseases vol 64 no 5 pp 708ndash714 2005
[90] J M Kahlenberg ldquoAnti-inflammatory panaceaThe expandingtherapeutics of interleukin-1 blockaderdquo Current Opinion inRheumatology vol 28 no 3 pp 197ndash203 2016
[91] C-H Chien M-J Lee H-C Liou H-H Liou and W-MFu ldquoLocal immunosuppressive microenvironment enhancesmigration of melanoma cells to lungs in DJ-1 knockout micerdquoPLoS ONE vol 10 no 2 Article ID e0115827 2015
[92] C Antonopoulos and G R Dubyak ldquoChemotherapy engagesmultiple pathways leading to IL-1120573 production by myeloidleukocytesrdquo OncoImmunology vol 3 no 1 Article ID e274992014
[93] E Ozaki M Campbell and S L Doyle ldquoTargeting the NLRP3inflammasome in chronic inflammatory diseases current per-spectivesrdquo Journal of Inflammation Research vol 8 pp 15ndash272015
[94] J H Hamman ldquoComposition and applications of Aloe vera leafgelrdquoMolecules vol 13 no 8 pp 1599ndash1616 2008
[95] L Langmead R J Makins and D S Rampton ldquoAnti-inflammatory effects of aloe vera gel in human colorectalmucosa in vitrordquo Alimentary Pharmacology and Therapeuticsvol 19 no 5 pp 521ndash527 2004
[96] N Yun C-H Lee and S-M Lee ldquoProtective effect of Aloe veraon polymicrobial sepsis inmicerdquo Food andChemical Toxicologyvol 47 no 6 pp 1341ndash1348 2009
[97] C S Yu F S Yu J K Chan et al ldquoAloe-emodin affects the levelsof cytokines and functions of leukocytes from Sprague-Dawleyratsrdquo In Vivo vol 20 no 4 pp 505ndash509 2006
[98] M Pulido-Moran J Moreno-Fernandez C Ramirez-Tortosaand M Ramirez-Tortosa ldquoCurcumin and healthrdquo Moleculesvol 21 no 3 article E264 2016
[99] Y-F Dong L-X Wang X Huang et al ldquoKir61 knock-down aggravates cerebral ischemiareperfusion-induced neuralinjury in micerdquo CNS Neuroscience and Therapeutics vol 19 no8 pp 617ndash624 2013
[100] P J Maier K Zemoura M A Acuna G E Yevenes HU Zeilhofer and D Benke ldquoIschemia-like oxygen and glu-cose deprivation mediates down-regulation of cell surface 120574-aminobutyric acidB receptors via the endoplasmic reticulum(ER) stress-induced transcription factor CCAATenhancer-binding protein (CEBP)-homologous protein (CHOP)rdquo TheJournal of Biological Chemistry vol 289 no 18 pp 12896ndash129072014
[101] H-Y Shin S-H Kim H-J Jeong et al ldquoEpigallocatechin-3-gallate inhibits secretion of TNF-120572 IL-6 and IL-8 through theattenuation of ERK and NF-120581B in HMC-1 cellsrdquo InternationalArchives of Allergy and Immunology vol 142 no 4 pp 335ndash3442007
[102] W P Pulskens L M Butter G J Teske et al ldquoNlrp3 preventsearly renal interstitial edema and vascular permeability inunilateral ureteral obstructionrdquo PLoS ONE vol 9 no 1 ArticleID e85775 2014
[103] S Kamath and C A Roobottom ldquoHyperdense pericardial effu-sion in dermatomyositis and contrast induced nephropathyrdquoEmergency Radiology vol 11 no 3 pp 177ndash179 2005
[104] T Akao K Kobashi and M Aburada ldquoEnzymic studies onthe animal and intestinal bacterial metabolism of geniposiderdquoBiological and Pharmaceutical Bulletin vol 17 no 12 pp 1573ndash1576 1994
[105] R Wang K C MoYung M H Zhang and K Poon ldquoUCP2-and non-UCP2-mediated electric current in eukaryotic cellsexhibits different propertiesrdquo Environmental Science and Pollu-tion Research vol 22 no 24 pp 19618ndash19631 2015
[106] J-M Lu Q Yao and C Chen ldquoGinseng compounds an updateon their molecular mechanisms and medical applicationsrdquoCurrent Vascular Pharmacology vol 7 no 3 pp 293ndash302 2009
[107] E Hernandez-Cuellar K Tsuchiya H Hara et al ldquoCuttingedge nitric oxide inhibits the NLRP3 inflammasomerdquo TheJournal of Immunology vol 189 no 11 pp 5113ndash5117 2012
[108] B B Mishra V A K Rathinam G W Martens et alldquoNitric oxide controls the immunopathology of tuberculosis byinhibiting NLRP3 inflammasome-dependent processing of IL-1120573rdquo Nature Immunology vol 14 no 1 pp 52ndash60 2013
[109] T Matsuno S-K Jung Y Matsumoto M Saito and JMorikawa ldquoPreferential cytotoxicity to tumor cells of 35-diprenyl-4-hydroxycinnamic acid (artepillin C) isolated frompropolisrdquo Anticancer Research vol 17 no 5A pp 3565ndash35681997
16 Mediators of Inflammation
[110] X Zhang J-H Zhang X-Y Chen et al ldquoReactive oxy-gen species-induced TXNIP drives fructose-mediated hepaticinflammation and lipid accumulation through NLRP3 inflam-masome activationrdquo Antioxidants and Redox Signaling vol 22no 10 pp 848ndash870 2015
[111] A Zendedel S Johann S Mehrabi et al ldquoActivation and reg-ulation of NLRP3 inflammasome by intrathecal application ofSDF-1a in a spinal cord injury modelrdquoMolecular Neurobiologyvol 53 no 5 pp 3063ndash3075 2016
[112] H Inoue and R Nakata ldquoResveratrol targets in inflammationrdquoEndocrineMetabolic and ImmuneDisordersmdashDrug Targets vol15 no 3 pp 186ndash195 2015
[113] S S Kulkarni and C Canto ldquoThe molecular targets of resver-atrolrdquo Biochimica et Biophysica Acta (BBA)mdashMolecular Basis ofDisease vol 1852 no 6 pp 1114ndash1123 2015
[114] C A Houghton R G Fassett and J S Coombes ldquoSul-foraphane translational research from laboratory bench toclinicrdquo Nutrition Reviews vol 71 no 11 pp 709ndash726 2013
[115] A T Dinkova-Kostova W D Holtzclaw R N Cole et alldquoDirect evidence that sulfhydryl groups of Keap1 are the sensorsregulating induction of phase 2 enzymes that protect againstcarcinogens and oxidantsrdquo Proceedings of the National Academyof Sciences of the United States of America vol 99 no 18 pp11908ndash11913 2002
[116] E Heiss C Herhaus K Klimo H Bartsch and C GerhauserldquoNuclear factor 120581B is a molecular target for sulforaphane-mediated anti-inflammatory mechanismsrdquo The Journal of Bio-logical Chemistry vol 276 no 34 pp 32008ndash32015 2001
[117] A Alfieri S Srivastava R C M Siow et al ldquoSulforaphanepreconditioning of the Nrf2HO-1 defense pathway protectsthe cerebral vasculature against blood-brain barrier disruptionand neurological deficits in strokerdquo Free Radical Biology andMedicine vol 65 pp 1012ndash1022 2013
[118] C Lee G H Park S-R Lee and J-H Jang ldquoAttenuation of120573 -amyloid-induced oxidative cell death by sulforaphane viaactivation of NF-E2-related factor 2rdquo Oxidative Medicine andCellular Longevity vol 2013 Article ID 313510 12 pages 2013
[119] E Barrajon-Catalan M Herranz-Lopez J Joven et al ldquoMolec-ular promiscuity of plant polyphenols in the management ofage-related diseases far beyond their antioxidant propertiesrdquoAdvances in Experimental Medicine and Biology vol 824 pp141ndash159 2014
[120] L Bravo ldquoPolyphenols chemistry dietary sources metabolismand nutritional significancerdquo Nutrition Reviews vol 56 no 11pp 317ndash333 1998
[121] D W Lamming J G Wood and D A Sinclair ldquoSmallmolecules that regulate lifespan evidence for xenohormesisrdquoMolecular Microbiology vol 53 no 4 pp 1003ndash1009 2004
[122] K T Howitz and D A Sinclair ldquoXenohormesis sensing thechemical cues of other speciesrdquo Cell vol 133 no 3 pp 387ndash3912008
[123] P L Hooper P L Hooper M Tytell and L Vıgh ldquoXeno-hormesis health benefits from an eon of plant stress responseevolutionrdquoCell Stress and Chaperones vol 15 no 6 pp 761ndash7702010
[124] B L Queen and T O Tollefsbol ldquoPolyphenols and agingrdquoCurrent Aging Science vol 3 no 1 pp 34ndash42 2010
[125] J A Baur and D A Sinclair ldquoTherapeutic potential of resvera-trol the in vivo evidencerdquo Nature Reviews Drug Discovery vol5 no 6 pp 493ndash506 2006
[126] R A Sharma A J Gescher and W P Steward ldquoCurcumin thestory so farrdquoEuropean Journal of Cancer vol 41 no 13 pp 1955ndash1968 2005
[127] K Milton ldquoMicronutrient intakes of wild primates are humansdifferentrdquo Comparative Biochemistry and Physiology Part AMolecular amp Integrative Physiology vol 136 no 1 pp 47ndash592003
inhibits NF120581B transcriptional activity through deacetylationthat in turn limits the transcription of NLRP3
In another study it was shown that cis-resveratrol pre-treatment significantly inhibited IL-1120573 secretion in THP-1 cellculture supernatants interestingly cis-resveratrol inducedIL-18 secretion under these conditions [71] Accordingly cis-resveratrol significantly reduced IL-1120573 mRNA expressionin contrast cis-resveratrol used at the same concentra-tion increased IL-18 mRNA expression Furthermore cis-resveratrol increased the mRNA and protein levels of NLRP1and NLRP3 indicating that the inhibitory effect of cis-resveratrol on IL-1120573 secretion is not due to the down-regulation of NLRP1 NLRP3 or ASC expression Similarresults were obtained on LPS-primed J774A1 macrophageswhere resveratrol inhibited the ATP-induced IL-1120573 secretionhowever in this study the authors did not find changes in theexpression of NLRP3 [72] showing that the resveratrol didnot inhibit the priming signal of NLRP3
Huang et al suggested that the inhibitory effect of cis-resveratrol on IL-1120573 secretion may be due to the reducedexpression of purinergic receptor P2X7R and the ER stressmarker GRP78 which leads to suppression of ROS pro-duction and reduced caspase-1 and caspase-4 activation Itwas found that cis-resveratrol also inhibited cyclooxygenase-(COX-) 2 expression which may be responsible for theobserved decrease of PGE2 production Furthermore inhi-bition of pro-IL-1120573 and COX-2 expression may occur bydownregulating the activation of the p38 MAPK path-way [71] Importantly in contrast to these observationsincreased phosphorylation of p38 was detected in ATP-activated J774A1 macrophages by Chang et al while itdid not significantly increase the phosphorylation levelsof ERK12 and it reduced the phosphorylation levels ofJNK12 The levels of mtDNA release into the cytosol weresignificantly reduced by resveratrol indicating that therewas less mitochondrial injury in resveratrol-treated cells[72] Furthermore the authors also showed that resveratrolincreased cellular cAMP level in J774A1 macrophages whichacts as a negative regulator of inflammatory responses andinhibits NLRP3 inflammasome activation
The effect of resveratrol on NLRP3 inflammasome wasfurther proved by a study showing that four weeks ofresveratrol administration inhibited the expression of NLRP3inflammasome components IL-1 IL-6 and TNF120572 and inlivers of HF-fed mice [73] They also showed that theregulatory effects of resveratrol on NLRP3 inflammasomemay come about through the combined effects of Sirt1 andSirt6
In a recent study [50] it was found that resveratroltreatment successfully suppressed the maturation of bothIL-1120573 and caspase-1 in response to Pam3CSK4 a TLR12agonist plus various inducers (like nigericin ATP MSUand silica) of the NLRP3-inflammasome In mouse BMDMshowever it did not affect the production of IL-1120573 medi-ated by the NLRC4-inflammasome (flagellin) or the AIM2-inflammasome (dsDNA) On a mouse model of acute goutthey indicated that resveratrol reduced the amount of matureIL-1120573 and the subsequent recruitment of neutrophils intothe peritoneal cavities of mice after challenge with MSU
crystals These findings indicate that resveratrol suppressesthe activation of the NLRP3-inflammasome both in vitroand in vivo As a possible mechanism they showed thatresveratrol at a substantially higher dosage successfullysuppressed mitochondrial ROS production Furthermoreresveratrol treatment prevented the accumulation of acety-lated 120572-tubulin thusinhibiting the proximate localization ofASC and NLRP3 in macrophages
In a very recent publication [74] the authors showed thatresveratrol preventedATP-inducedNLRP3 activation and IL-1120573 production in the BV2 cell line and in septic mice as wellThey also found that resveratrol treatment reduced NLRP3and IL-1120573 expression in the hippocampus of the mice andthey suggested that the protecting effect of resveratrol wasmediated via the increased expression of Sirt1 in BV2 cells
Another recent publication found that glucose-basedperitoneal dialysis increased mitochondrial ROS productionand subsequent IL-1120573 secretion through NLRP3 inflamma-some in human peritoneal mesothelial cells (HPMC) Asa mechanism for its action they showed that resveratrolinduced mitophagyautophagy of the cells via AMPK activa-tion and protected cells fromROS-inducedNLRP3-mediatedinflammatory injury [75]
410 Sulforaphane Sulforaphane (SFN) is a natural com-pound present in cruciferous vegetables such as broccolicabbage Brussel sprouts mustard and radish ChemicallySFN is an isothiocyanate that is known to react withsulfhydryl groups and tomodify proteins at cysteine residuesSulforaphane is produced from the precursor glucoraphaninby the enzymatic activity of myrosinase when the cell wallsof the plant are damaged for example during chewingSFN has been known as a cytoprotective agent for cancerprevention or treatment and it also has an important rolein cardiovascular neurologic and other diseases (reviewedin [114]) SFN is a known inducer of the Nrf2 antioxidantpathway as it activates the Nrf2 transcription factor byreacting with cysteine residues of its repressor Keap1 [115]In addition it also inhibits NF120581B signaling [116]
It was shown that SFN inhibited IL-1120573 processing byNLRP1- NLRP3- NLRC4- and AIM2- inflammasome com-plexes in mouse BMDMs [28] It was also demonstratedthat SFN inhibits the inflammasome in an Nrf2-independentmanner as SFN-mediated inhibition of NLRP3- andNLRC4-dependent IL-1120573 processing and secretion was not reversedin Nrf2-knockout BMDMs When SFN was added directlyto the cell lysates it did not inhibit IL-1120573 processingdemonstrating that SFN does not directly inhibit the proteaseactivity of caspase-1 The authors found that SFN-mediatedinhibition of the inflammasomes is not affected by ROSmodulation and neither proteasome-dependent proteolysisnor de novo protein synthesis is required for SFN-mediatedinhibition of the inflammasomes In a peritonitis model ofacute gout SFN treatment significantly reducedMSU crystal-induced IL-1120573 production demonstrating that SFN inhibitsthe NLRP3 inflammasome function in vivo Nonethelessthe authors concluded that SFN inhibits multiple inflam-masomes in vitro and in vivo by a mechanism independent
Mediators of Inflammation 11
ERKp38
NLRP3
ASCNLRP3
Caspase-1ROS
ER stress
P2X7R ATP
Cathepsin B
TLR
ROS
mtDNA
Sirt2
AcAc
AcAc
AMPK
A
A AC
C
C
Nrf2E
E
UCP2Ge
Ge
Ge
Gi
TXNIPC
NOGi
P
Sirt1R
R
R
R
M
M
M
Q
QQ
SS
S
R
Cardio-lipin
Acetylated 120572-tubulin
Ca2+ influx
IL-1120573
Pro-IL-1120573
K+efflux
120572-Tubulin
Pro-IL-1120573
NF120581B
Figure 3 Molecular targets of natural compounds affecting NLRP3 inflammasome-mediated IL-1 production
of inflammasome priming and Nrf2 signaling however theexact molecular mechanism was not explored
As SFN is able to penetrate the blood-brain barrier[117] it gained a considerable attention as a candidatefor Alzheimerrsquos disease (AD) therapy SFN was shown toprotect the brain from A120573-induced oxidative cell death viaactivation of Nrf2 signaling cascade [118] As A120573 fibrilshave been shown to activate NLRP3 inflammasome thequestion arose whether SFN may regulate this mechanismIn a very recent study it was shown that SFN significantlydownregulated IL-1120573 production and NLRP3 expression inA1205731ndash42 peptide-stimulated human THP-1 cells macrophages[76] It was found that A1205731ndash42 peptide-induced STAT-1phosphorylation was significantly attenuated by SFN Theauthors showed that SFN inducedNrf2 nuclear translocationwhich was subsequently accompanied by an increase in HO-1 protein levels Furthermore A1205731ndash42 peptide-induced IL-1120573 production was diminished by siRNA-mediated knock-down of Nrf2 or HO-1 They also found that the increasedproinflammatory miRNA-146a level following A1205731ndash42 treat-ment was significantly attenuated by SFN whereas miRNA-125b and miRNA-155 levels were not changed These arespecific proinflammatory miRNAs that were reported to beincreased in both the extracellular fluid and cerebrospinalfluid of AD patients In conclusion SFN can suppress A1205731ndash42-induced caspase-1-dependent inflammasome activationpossibly through inhibiting STAT-1 phosphorylation andactivation of the Nrf2HO-1 signaling pathway
Also very recently another research group reported thatoral administrations of SFN suppressed the saturated fattyacid-induced NLRP3 inflammasome activation in the liverof mice [77] They found that SFN decreased the expression
of ASC caspase-1 and IL-1120573 levels additionally it inhibitedthe activity of caspase-1 enzyme in primary hepatocytes Itwas also shown that SFN reduced the palmitate-inducedROS production by the mitochondria implying that SFNprevented mitochondrial dysfunction and this protectingmechanism was in part mediated by the activation of AMPKThey concluded that activation of AMPK and autophagy bySFN could protect from mitochondrial dysfunction inducedby saturated fatty acids resulting in a downregulation of fat-induced activation of the NLRP3 inflammasome
5 NLRP3 Inflammasome and theXenohormesis Hypothesis
As it was described in detail above polyphenols like resvera-trol curcumin EGCG and quercetin are potent inhibitors ofNLRP3 inflammasome-mediated IL-1120573 production typicallyacting at more than one element of the involved pathways(Figure 3)However it should be noted that these polyphenolshave an evenmuch broader biological effect as they influencea variety of pathways [119] though not all are directlyconnected to the function of the NLRP3 inflammasomeImportantly more than 8000 natural polyphenols have beendescribed [120] providing a large library of compounds aspotential inflammasome inhibitors Many of these polyphe-nols (such as resveratrol and curcumin) are overproducedby stressed plants triggering pathways mimicking the effectof caloric restriction It has been proposed that organismsfrom yeast to humans consuming stressed plants couldinterpret the stress signal carried by such polyphenols as apotential risk of future limitation of food availability and in
12 Mediators of Inflammation
turn adapting for the pursuit of longevity a theory termedas Xenohormesis [121ndash123] Interestingly the structurallyunrelated resveratrol and curcumin can achieve this caloricrestriction mimicking effect by activating AMPK and Sirt1[124] However polyphenols are also known to have anantioxidant effect activate glutathione S-transferases andinhibit COX enzymes among many other effects [125 126]Interestingly one of the most frequently used COX inhibitoris aspirin a derivative of another stress-induced phytochem-ical salicylic acid
A major concern of polyphenol use in therapy is thebioavailability of these compounds Nevertheless typicaldietary polyphenol intake is about 14mgkgday which iswithin the range of providing biologically active doses [127]
6 Concluding Remarks
Most of the time inflammasome-mediated IL-1120573 productionor caspase-mediated pyroptosis is beneficial for the host as itprotects from infection or prevents further damageHoweverprolonged cytokine production as in the case of sterileinflammation caused by endogenous danger signals maylead to the development of autoinflammatory or metabolicdiseases Chronic inflammation compromises the hostrsquos lifequality and requires sustained pharmacological and surgicaltreatments The paradigm of drug discovery in Westernmedicine is to develop highly selective compounds againstindividual druggable targets Currently the main treatmentmethods for these patients are targeting IL-1120573 Howeverprolonged usage of drugs may induce different side effectsfurthermore some form of medications are very expensivewhich limits their widespread use
Besides the high expenses another drawback of tradi-tional drug design is that many of the promising compoundsfail in the early or later stages of drug development Tradi-tional medicine uses many plant products to treat diseaseshowever the exact mechanisms behind their use is stillmostly lacking partially as a consequence of the pleiotropiceffect of the active compounds as detailed in this reviewNevertheless clarification of the molecular mechanism ofaction of such natural compounds already used in traditionalmedicine for quite some time will undoubtedly aid in theproduction of safe and cheap candidate medications to beused in the treatment of diseases including those appearingas a consequence of NLRP3 inflammasome-mediated IL-1120573overproduction
Competing Interests
The authors declare no conflict of interests
Acknowledgments
This work was supported by OTKA-K 109429 Szilvia Benkois a receiver of Lajos Szodoray Postdoctoral Fellowship andJanos Bolyai Postdoctoral Fellowship
References
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[2] G Meng F Zhang I Fuss A Kitani and W Strober ldquoA muta-tion in the Nlrp3 gene causing inflammasome hyperactivationpotentiates Th17 cell-dominant immune responsesrdquo Immunityvol 30 no 6 pp 860ndash874 2009
[3] D Lasiglie E Traggiai S Federici et al ldquoRole of IL-1 beta in thedevelopment of human TH17 cells lesson fromNLPR3mutatedpatientsrdquo PLoS ONE vol 6 no 5 Article ID e20014 2011
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[5] E Gabay G Wolf Y Shavit R Yirmiya and M Tal ldquoChronicblockade of interleukin-1 (IL-1) prevents and attenuates neuro-pathic pain behavior and spontaneous ectopic neuronal activityfollowing nerve injuryrdquo European Journal of Pain vol 15 no 3pp 242ndash248 2011
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[47] N Subramanian K Natarajan M R Clatworthy Z Wangand R N Germain ldquoThe adaptor MAVS promotes NLRP3mitochondrial localization and inflammasome activationrdquo Cellvol 153 no 2 pp 348ndash361 2013
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14 Mediators of Inflammation
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[51] M M Budai A Varga S Milesz J Tozser and S BenkoldquoAloe vera downregulates LPS-induced inflammatory cytokineproduction and expression of NLRP3 inflammasome in humanmacrophagesrdquo Molecular Immunology vol 56 no 4 pp 471ndash479 2013
[52] J-W Han D-W Shim W-Y Shin et al ldquoAnti-inflammatoryeffect of emodin via attenuation of NLRP3 inflammasomeactivationrdquo International Journal of Molecular Sciences vol 16no 4 pp 8102ndash8109 2015
[53] Y Li J Li S Li et al ldquoCurcumin attenuates glutamate neurotox-icity in the hippocampus by suppression of ER stress-associatedTXNIPNLRP3 inflammasome activation in a manner depen-dent onAMPKrdquoToxicology andApplied Pharmacology vol 286no 1 pp 53ndash63 2015
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[69] W Jiang Y Huang N Han et al ldquoQuercetin suppresses NLRP3inflammasome activation and attenuates histopathology in a ratmodel of spinal cord injuryrdquo Spinal Cord vol 54 pp 592ndash5962016
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[71] T-T Huang H-C Lai Y-B Chen et al ldquoCis-Resveratrolproduces anti-inflammatory effects by inhibiting canonicaland non-canonical inflammasomes in macrophagesrdquo InnateImmunity vol 20 no 7 pp 735ndash750 2014
[72] Y-P Chang S-M Ka W-H Hsu et al ldquoResveratrol inhibitsNLRP3 inflammasome activation by preserving mitochondrialintegrity and augmenting autophagyrdquo Journal of Cellular Physi-ology vol 230 no 7 pp 1567ndash1579 2015
[73] S J Yang and Y Lim ldquoResveratrol ameliorates hepaticmetaflammation and inhibits NLRP3 inflammasome activa-tionrdquoMetabolism vol 63 no 5 pp 693ndash701 2014
[74] D-M Sui Q Xie W-J Yi et al ldquoResveratrol protects againstsepsis-associated encephalopathy and inhibits the NLRP3IL-1 120573 axis in microgliardquo Mediators of Inflammation vol 2016Article ID 1045657 10 pages 2016
[75] J Wu X Li G Zhu Y Zhang M He and J Zhang ldquoTherole of Resveratrol-inducedmitophagyautophagy in peritonealmesothelial cells inflammatory injury via NLRP3 inflamma-some activation triggered bymitochondrial ROSrdquoExperimentalCell Research vol 341 no 1 pp 42ndash53 2016
[76] Y W An K A Jhang S Y Woo J L Kang and Y HChong ldquoSulforaphane exerts its anti-inflammatory effectagainst amyloid-120573 peptide via STAT-1 dephosphorylationand activation of Nrf2HO-1 cascade in human THP-1macrophagesrdquo Neurobiology of Aging vol 38 pp 1ndash10 2016
[77] G Yang H E Lee and J Y Lee ldquoA pharmacological inhibitorof NLRP3 inflammasome prevents non-alcoholic fatty liver
Mediators of Inflammation 15
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[79] S L Cassel and F S Sutterwala ldquoSterile inflammatory responsesmediated by the NLRP3 inflammasomerdquo European Journal ofImmunology vol 40 no 3 pp 607ndash611 2010
[80] M-S Tan J-T Yu T Jiang X-C Zhu and L Tan ldquoThe NLRP3inflammasome in alzheimerrsquos diseaserdquoMolecular Neurobiologyvol 48 no 3 pp 875ndash882 2013
[81] M Gold and J El Khoury ldquo120573-amyloid microglia andthe inflammasome in Alzheimerrsquos diseaserdquo Seminars inImmunopathology vol 37 no 6 pp 607ndash611 2015
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[84] X Dai K Sayama M Tohyama et al ldquoMite allergen is adanger signal for the skin via activation of inflammasome inkeratinocytesrdquo Journal of Allergy and Clinical Immunology vol127 no 3 pp 806ndash814 2011
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[89] S Rosengren H M Hoffman W Bugbee and D L BoyleldquoExpression and regulation of cryopyrin and related proteinsin rheumatoid arthritis synoviumrdquo Annals of the RheumaticDiseases vol 64 no 5 pp 708ndash714 2005
[90] J M Kahlenberg ldquoAnti-inflammatory panaceaThe expandingtherapeutics of interleukin-1 blockaderdquo Current Opinion inRheumatology vol 28 no 3 pp 197ndash203 2016
[91] C-H Chien M-J Lee H-C Liou H-H Liou and W-MFu ldquoLocal immunosuppressive microenvironment enhancesmigration of melanoma cells to lungs in DJ-1 knockout micerdquoPLoS ONE vol 10 no 2 Article ID e0115827 2015
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[94] J H Hamman ldquoComposition and applications of Aloe vera leafgelrdquoMolecules vol 13 no 8 pp 1599ndash1616 2008
[95] L Langmead R J Makins and D S Rampton ldquoAnti-inflammatory effects of aloe vera gel in human colorectalmucosa in vitrordquo Alimentary Pharmacology and Therapeuticsvol 19 no 5 pp 521ndash527 2004
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[97] C S Yu F S Yu J K Chan et al ldquoAloe-emodin affects the levelsof cytokines and functions of leukocytes from Sprague-Dawleyratsrdquo In Vivo vol 20 no 4 pp 505ndash509 2006
[98] M Pulido-Moran J Moreno-Fernandez C Ramirez-Tortosaand M Ramirez-Tortosa ldquoCurcumin and healthrdquo Moleculesvol 21 no 3 article E264 2016
[99] Y-F Dong L-X Wang X Huang et al ldquoKir61 knock-down aggravates cerebral ischemiareperfusion-induced neuralinjury in micerdquo CNS Neuroscience and Therapeutics vol 19 no8 pp 617ndash624 2013
[100] P J Maier K Zemoura M A Acuna G E Yevenes HU Zeilhofer and D Benke ldquoIschemia-like oxygen and glu-cose deprivation mediates down-regulation of cell surface 120574-aminobutyric acidB receptors via the endoplasmic reticulum(ER) stress-induced transcription factor CCAATenhancer-binding protein (CEBP)-homologous protein (CHOP)rdquo TheJournal of Biological Chemistry vol 289 no 18 pp 12896ndash129072014
[101] H-Y Shin S-H Kim H-J Jeong et al ldquoEpigallocatechin-3-gallate inhibits secretion of TNF-120572 IL-6 and IL-8 through theattenuation of ERK and NF-120581B in HMC-1 cellsrdquo InternationalArchives of Allergy and Immunology vol 142 no 4 pp 335ndash3442007
[102] W P Pulskens L M Butter G J Teske et al ldquoNlrp3 preventsearly renal interstitial edema and vascular permeability inunilateral ureteral obstructionrdquo PLoS ONE vol 9 no 1 ArticleID e85775 2014
[103] S Kamath and C A Roobottom ldquoHyperdense pericardial effu-sion in dermatomyositis and contrast induced nephropathyrdquoEmergency Radiology vol 11 no 3 pp 177ndash179 2005
[104] T Akao K Kobashi and M Aburada ldquoEnzymic studies onthe animal and intestinal bacterial metabolism of geniposiderdquoBiological and Pharmaceutical Bulletin vol 17 no 12 pp 1573ndash1576 1994
[105] R Wang K C MoYung M H Zhang and K Poon ldquoUCP2-and non-UCP2-mediated electric current in eukaryotic cellsexhibits different propertiesrdquo Environmental Science and Pollu-tion Research vol 22 no 24 pp 19618ndash19631 2015
[106] J-M Lu Q Yao and C Chen ldquoGinseng compounds an updateon their molecular mechanisms and medical applicationsrdquoCurrent Vascular Pharmacology vol 7 no 3 pp 293ndash302 2009
[107] E Hernandez-Cuellar K Tsuchiya H Hara et al ldquoCuttingedge nitric oxide inhibits the NLRP3 inflammasomerdquo TheJournal of Immunology vol 189 no 11 pp 5113ndash5117 2012
[108] B B Mishra V A K Rathinam G W Martens et alldquoNitric oxide controls the immunopathology of tuberculosis byinhibiting NLRP3 inflammasome-dependent processing of IL-1120573rdquo Nature Immunology vol 14 no 1 pp 52ndash60 2013
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16 Mediators of Inflammation
[110] X Zhang J-H Zhang X-Y Chen et al ldquoReactive oxy-gen species-induced TXNIP drives fructose-mediated hepaticinflammation and lipid accumulation through NLRP3 inflam-masome activationrdquo Antioxidants and Redox Signaling vol 22no 10 pp 848ndash870 2015
[111] A Zendedel S Johann S Mehrabi et al ldquoActivation and reg-ulation of NLRP3 inflammasome by intrathecal application ofSDF-1a in a spinal cord injury modelrdquoMolecular Neurobiologyvol 53 no 5 pp 3063ndash3075 2016
[112] H Inoue and R Nakata ldquoResveratrol targets in inflammationrdquoEndocrineMetabolic and ImmuneDisordersmdashDrug Targets vol15 no 3 pp 186ndash195 2015
[113] S S Kulkarni and C Canto ldquoThe molecular targets of resver-atrolrdquo Biochimica et Biophysica Acta (BBA)mdashMolecular Basis ofDisease vol 1852 no 6 pp 1114ndash1123 2015
[114] C A Houghton R G Fassett and J S Coombes ldquoSul-foraphane translational research from laboratory bench toclinicrdquo Nutrition Reviews vol 71 no 11 pp 709ndash726 2013
[115] A T Dinkova-Kostova W D Holtzclaw R N Cole et alldquoDirect evidence that sulfhydryl groups of Keap1 are the sensorsregulating induction of phase 2 enzymes that protect againstcarcinogens and oxidantsrdquo Proceedings of the National Academyof Sciences of the United States of America vol 99 no 18 pp11908ndash11913 2002
[116] E Heiss C Herhaus K Klimo H Bartsch and C GerhauserldquoNuclear factor 120581B is a molecular target for sulforaphane-mediated anti-inflammatory mechanismsrdquo The Journal of Bio-logical Chemistry vol 276 no 34 pp 32008ndash32015 2001
[117] A Alfieri S Srivastava R C M Siow et al ldquoSulforaphanepreconditioning of the Nrf2HO-1 defense pathway protectsthe cerebral vasculature against blood-brain barrier disruptionand neurological deficits in strokerdquo Free Radical Biology andMedicine vol 65 pp 1012ndash1022 2013
[118] C Lee G H Park S-R Lee and J-H Jang ldquoAttenuation of120573 -amyloid-induced oxidative cell death by sulforaphane viaactivation of NF-E2-related factor 2rdquo Oxidative Medicine andCellular Longevity vol 2013 Article ID 313510 12 pages 2013
[119] E Barrajon-Catalan M Herranz-Lopez J Joven et al ldquoMolec-ular promiscuity of plant polyphenols in the management ofage-related diseases far beyond their antioxidant propertiesrdquoAdvances in Experimental Medicine and Biology vol 824 pp141ndash159 2014
[120] L Bravo ldquoPolyphenols chemistry dietary sources metabolismand nutritional significancerdquo Nutrition Reviews vol 56 no 11pp 317ndash333 1998
[121] D W Lamming J G Wood and D A Sinclair ldquoSmallmolecules that regulate lifespan evidence for xenohormesisrdquoMolecular Microbiology vol 53 no 4 pp 1003ndash1009 2004
[122] K T Howitz and D A Sinclair ldquoXenohormesis sensing thechemical cues of other speciesrdquo Cell vol 133 no 3 pp 387ndash3912008
[123] P L Hooper P L Hooper M Tytell and L Vıgh ldquoXeno-hormesis health benefits from an eon of plant stress responseevolutionrdquoCell Stress and Chaperones vol 15 no 6 pp 761ndash7702010
[124] B L Queen and T O Tollefsbol ldquoPolyphenols and agingrdquoCurrent Aging Science vol 3 no 1 pp 34ndash42 2010
[125] J A Baur and D A Sinclair ldquoTherapeutic potential of resvera-trol the in vivo evidencerdquo Nature Reviews Drug Discovery vol5 no 6 pp 493ndash506 2006
[126] R A Sharma A J Gescher and W P Steward ldquoCurcumin thestory so farrdquoEuropean Journal of Cancer vol 41 no 13 pp 1955ndash1968 2005
[127] K Milton ldquoMicronutrient intakes of wild primates are humansdifferentrdquo Comparative Biochemistry and Physiology Part AMolecular amp Integrative Physiology vol 136 no 1 pp 47ndash592003
Figure 3 Molecular targets of natural compounds affecting NLRP3 inflammasome-mediated IL-1 production
of inflammasome priming and Nrf2 signaling however theexact molecular mechanism was not explored
As SFN is able to penetrate the blood-brain barrier[117] it gained a considerable attention as a candidatefor Alzheimerrsquos disease (AD) therapy SFN was shown toprotect the brain from A120573-induced oxidative cell death viaactivation of Nrf2 signaling cascade [118] As A120573 fibrilshave been shown to activate NLRP3 inflammasome thequestion arose whether SFN may regulate this mechanismIn a very recent study it was shown that SFN significantlydownregulated IL-1120573 production and NLRP3 expression inA1205731ndash42 peptide-stimulated human THP-1 cells macrophages[76] It was found that A1205731ndash42 peptide-induced STAT-1phosphorylation was significantly attenuated by SFN Theauthors showed that SFN inducedNrf2 nuclear translocationwhich was subsequently accompanied by an increase in HO-1 protein levels Furthermore A1205731ndash42 peptide-induced IL-1120573 production was diminished by siRNA-mediated knock-down of Nrf2 or HO-1 They also found that the increasedproinflammatory miRNA-146a level following A1205731ndash42 treat-ment was significantly attenuated by SFN whereas miRNA-125b and miRNA-155 levels were not changed These arespecific proinflammatory miRNAs that were reported to beincreased in both the extracellular fluid and cerebrospinalfluid of AD patients In conclusion SFN can suppress A1205731ndash42-induced caspase-1-dependent inflammasome activationpossibly through inhibiting STAT-1 phosphorylation andactivation of the Nrf2HO-1 signaling pathway
Also very recently another research group reported thatoral administrations of SFN suppressed the saturated fattyacid-induced NLRP3 inflammasome activation in the liverof mice [77] They found that SFN decreased the expression
of ASC caspase-1 and IL-1120573 levels additionally it inhibitedthe activity of caspase-1 enzyme in primary hepatocytes Itwas also shown that SFN reduced the palmitate-inducedROS production by the mitochondria implying that SFNprevented mitochondrial dysfunction and this protectingmechanism was in part mediated by the activation of AMPKThey concluded that activation of AMPK and autophagy bySFN could protect from mitochondrial dysfunction inducedby saturated fatty acids resulting in a downregulation of fat-induced activation of the NLRP3 inflammasome
5 NLRP3 Inflammasome and theXenohormesis Hypothesis
As it was described in detail above polyphenols like resvera-trol curcumin EGCG and quercetin are potent inhibitors ofNLRP3 inflammasome-mediated IL-1120573 production typicallyacting at more than one element of the involved pathways(Figure 3)However it should be noted that these polyphenolshave an evenmuch broader biological effect as they influencea variety of pathways [119] though not all are directlyconnected to the function of the NLRP3 inflammasomeImportantly more than 8000 natural polyphenols have beendescribed [120] providing a large library of compounds aspotential inflammasome inhibitors Many of these polyphe-nols (such as resveratrol and curcumin) are overproducedby stressed plants triggering pathways mimicking the effectof caloric restriction It has been proposed that organismsfrom yeast to humans consuming stressed plants couldinterpret the stress signal carried by such polyphenols as apotential risk of future limitation of food availability and in
12 Mediators of Inflammation
turn adapting for the pursuit of longevity a theory termedas Xenohormesis [121ndash123] Interestingly the structurallyunrelated resveratrol and curcumin can achieve this caloricrestriction mimicking effect by activating AMPK and Sirt1[124] However polyphenols are also known to have anantioxidant effect activate glutathione S-transferases andinhibit COX enzymes among many other effects [125 126]Interestingly one of the most frequently used COX inhibitoris aspirin a derivative of another stress-induced phytochem-ical salicylic acid
A major concern of polyphenol use in therapy is thebioavailability of these compounds Nevertheless typicaldietary polyphenol intake is about 14mgkgday which iswithin the range of providing biologically active doses [127]
6 Concluding Remarks
Most of the time inflammasome-mediated IL-1120573 productionor caspase-mediated pyroptosis is beneficial for the host as itprotects from infection or prevents further damageHoweverprolonged cytokine production as in the case of sterileinflammation caused by endogenous danger signals maylead to the development of autoinflammatory or metabolicdiseases Chronic inflammation compromises the hostrsquos lifequality and requires sustained pharmacological and surgicaltreatments The paradigm of drug discovery in Westernmedicine is to develop highly selective compounds againstindividual druggable targets Currently the main treatmentmethods for these patients are targeting IL-1120573 Howeverprolonged usage of drugs may induce different side effectsfurthermore some form of medications are very expensivewhich limits their widespread use
Besides the high expenses another drawback of tradi-tional drug design is that many of the promising compoundsfail in the early or later stages of drug development Tradi-tional medicine uses many plant products to treat diseaseshowever the exact mechanisms behind their use is stillmostly lacking partially as a consequence of the pleiotropiceffect of the active compounds as detailed in this reviewNevertheless clarification of the molecular mechanism ofaction of such natural compounds already used in traditionalmedicine for quite some time will undoubtedly aid in theproduction of safe and cheap candidate medications to beused in the treatment of diseases including those appearingas a consequence of NLRP3 inflammasome-mediated IL-1120573overproduction
Competing Interests
The authors declare no conflict of interests
Acknowledgments
This work was supported by OTKA-K 109429 Szilvia Benkois a receiver of Lajos Szodoray Postdoctoral Fellowship andJanos Bolyai Postdoctoral Fellowship
References
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[2] G Meng F Zhang I Fuss A Kitani and W Strober ldquoA muta-tion in the Nlrp3 gene causing inflammasome hyperactivationpotentiates Th17 cell-dominant immune responsesrdquo Immunityvol 30 no 6 pp 860ndash874 2009
[3] D Lasiglie E Traggiai S Federici et al ldquoRole of IL-1 beta in thedevelopment of human TH17 cells lesson fromNLPR3mutatedpatientsrdquo PLoS ONE vol 6 no 5 Article ID e20014 2011
[4] H Schneider F Pitossi D Balschun A Wagner A Del Reyand H O Besedovsky ldquoA neuromodulatory role of interleukin-1120573 in the hippocampusrdquo Proceedings of the National Academy ofSciences of the United States of America vol 95 no 13 pp 7778ndash7783 1998
[5] E Gabay G Wolf Y Shavit R Yirmiya and M Tal ldquoChronicblockade of interleukin-1 (IL-1) prevents and attenuates neuro-pathic pain behavior and spontaneous ectopic neuronal activityfollowing nerve injuryrdquo European Journal of Pain vol 15 no 3pp 242ndash248 2011
[6] A del Rey A V Apkarian M Martina and H O BesedovskyldquoChronic neuropathic pain-like behavior and brain-borne IL-1120573rdquo Annals of the New York Academy of Sciences vol 1262 no 1pp 101ndash107 2012
[7] R Yirmiya and I Goshen ldquoImmune modulation of learningmemory neural plasticity and neurogenesisrdquo Brain Behaviorand Immunity vol 25 no 2 pp 181ndash213 2011
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Mediators of Inflammation 13
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[37] D Perregaux and C A Gabel ldquoInterleukin-1 beta maturationand release in response to ATP and nigericin Evidence thatpotassium depletion mediated by these agents is a necessaryand common feature of their activityrdquoThe Journal of BiologicalChemistry vol 269 no 21 pp 15195ndash15203 1994
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[45] X Wang W Jiang Y Yan et al ldquoRNA viruses promoteactivation of the NLRP3 inflammasome through a RIP1-RIP3-DRP1 signaling pathwayrdquoNature Immunology vol 15 no 12 pp1126ndash1133 2014
[46] T Ichinohe T Yamazaki T Koshiba and Y Yanagi ldquoMitochon-drial protein mitofusin 2 is required for NLRP3 inflammasomeactivation afterRNAvirus infectionrdquoProceedings of theNationalAcademy of Sciences of the United States of America vol 110 no44 pp 17963ndash17968 2013
[47] N Subramanian K Natarajan M R Clatworthy Z Wangand R N Germain ldquoThe adaptor MAVS promotes NLRP3mitochondrial localization and inflammasome activationrdquo Cellvol 153 no 2 pp 348ndash361 2013
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14 Mediators of Inflammation
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[50] T Misawa M Takahama T Kozaki et al ldquoMicrotubule-drivenspatial arrangement ofmitochondria promotes activation of theNLRP3 inflammasomerdquo Nature Immunology vol 14 no 5 pp454ndash460 2013
[51] M M Budai A Varga S Milesz J Tozser and S BenkoldquoAloe vera downregulates LPS-induced inflammatory cytokineproduction and expression of NLRP3 inflammasome in humanmacrophagesrdquo Molecular Immunology vol 56 no 4 pp 471ndash479 2013
[52] J-W Han D-W Shim W-Y Shin et al ldquoAnti-inflammatoryeffect of emodin via attenuation of NLRP3 inflammasomeactivationrdquo International Journal of Molecular Sciences vol 16no 4 pp 8102ndash8109 2015
[53] Y Li J Li S Li et al ldquoCurcumin attenuates glutamate neurotox-icity in the hippocampus by suppression of ER stress-associatedTXNIPNLRP3 inflammasome activation in a manner depen-dent onAMPKrdquoToxicology andApplied Pharmacology vol 286no 1 pp 53ndash63 2015
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[55] P-Y Tsai S-M Ka J-M Chang et al ldquoEpigallocatechin-3-gallate prevents lupus nephritis development in mice viaenhancing the Nrf2 antioxidant pathway and inhibiting NLRP3inflammasome activationrdquo Free Radical Biology and Medicinevol 51 no 3 pp 744ndash754 2011
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[62] C-W Pan Z-Z Pan J-J Hu et al ldquoMangiferin alleviateslipopolysaccharide and D-galactosamine-induced acute liverinjury by activating the Nrf2 pathway and inhibiting NLRP3inflammasome activationrdquo European Journal of Pharmacologyvol 770 pp 85ndash91 2016
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[64] C Wang Y Pan Q-Y Zhang F-M Wang and L-D KongldquoQuercetin and allopurinol ameliorate kidney injury in STZ-treated rats with regulation of renal NLRP3 inflammasomeactivation and lipid accumulationrdquo PLoS ONE vol 7 no 6Article ID e38285 2012
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[66] WWangCWangX-QDing et al ldquoQuercetin and allopurinolreduce liver thioredoxin-interacting protein to alleviate inflam-mation and lipid accumulation in diabetic ratsrdquo British Journalof Pharmacology vol 169 no 6 pp 1352ndash1371 2013
[67] Q-Y Zhang Y Pan R Wang et al ldquoQuercetin inhibitsAMPKTXNIP activation and reduces inflammatory lesions toimprove insulin signaling defect in the hypothalamus of highfructose-fed ratsrdquo Journal of Nutritional Biochemistry vol 25no 4 pp 420ndash428 2014
[68] J Wu X Xu Y Li et al ldquoQuercetin luteolin and epigallo-catechin gallate alleviate TXNIP and NLRP3-mediated inflam-mation and apoptosis with regulation of AMPK in endothelialcellsrdquo European Journal of Pharmacology vol 745 pp 59ndash682015
[69] W Jiang Y Huang N Han et al ldquoQuercetin suppresses NLRP3inflammasome activation and attenuates histopathology in a ratmodel of spinal cord injuryrdquo Spinal Cord vol 54 pp 592ndash5962016
[70] Y Fu Y Wang L Du et al ldquoResveratrol inhibits ionisingirradiation-induced inflammation in MSCs by activating Sirt1and limiting NLRP-3 inflammasome activationrdquo InternationalJournal ofMolecular Sciences vol 14 no 7 pp 14105ndash14118 2013
[71] T-T Huang H-C Lai Y-B Chen et al ldquoCis-Resveratrolproduces anti-inflammatory effects by inhibiting canonicaland non-canonical inflammasomes in macrophagesrdquo InnateImmunity vol 20 no 7 pp 735ndash750 2014
[72] Y-P Chang S-M Ka W-H Hsu et al ldquoResveratrol inhibitsNLRP3 inflammasome activation by preserving mitochondrialintegrity and augmenting autophagyrdquo Journal of Cellular Physi-ology vol 230 no 7 pp 1567ndash1579 2015
[73] S J Yang and Y Lim ldquoResveratrol ameliorates hepaticmetaflammation and inhibits NLRP3 inflammasome activa-tionrdquoMetabolism vol 63 no 5 pp 693ndash701 2014
[74] D-M Sui Q Xie W-J Yi et al ldquoResveratrol protects againstsepsis-associated encephalopathy and inhibits the NLRP3IL-1 120573 axis in microgliardquo Mediators of Inflammation vol 2016Article ID 1045657 10 pages 2016
[75] J Wu X Li G Zhu Y Zhang M He and J Zhang ldquoTherole of Resveratrol-inducedmitophagyautophagy in peritonealmesothelial cells inflammatory injury via NLRP3 inflamma-some activation triggered bymitochondrial ROSrdquoExperimentalCell Research vol 341 no 1 pp 42ndash53 2016
[76] Y W An K A Jhang S Y Woo J L Kang and Y HChong ldquoSulforaphane exerts its anti-inflammatory effectagainst amyloid-120573 peptide via STAT-1 dephosphorylationand activation of Nrf2HO-1 cascade in human THP-1macrophagesrdquo Neurobiology of Aging vol 38 pp 1ndash10 2016
[77] G Yang H E Lee and J Y Lee ldquoA pharmacological inhibitorof NLRP3 inflammasome prevents non-alcoholic fatty liver
Mediators of Inflammation 15
disease in a mouse model induced by high fat dietrdquo ScientificReports vol 6 Article ID 24399 2016
[78] L Franchi R Munoz-Planillo and G Nunez ldquoSensing andreacting to microbes through the inflammasomesrdquo NatureImmunology vol 13 no 4 pp 325ndash332 2012
[79] S L Cassel and F S Sutterwala ldquoSterile inflammatory responsesmediated by the NLRP3 inflammasomerdquo European Journal ofImmunology vol 40 no 3 pp 607ndash611 2010
[80] M-S Tan J-T Yu T Jiang X-C Zhu and L Tan ldquoThe NLRP3inflammasome in alzheimerrsquos diseaserdquoMolecular Neurobiologyvol 48 no 3 pp 875ndash882 2013
[81] M Gold and J El Khoury ldquo120573-amyloid microglia andthe inflammasome in Alzheimerrsquos diseaserdquo Seminars inImmunopathology vol 37 no 6 pp 607ndash611 2015
[82] P M Peeters T N Perkins E F M Wouters B T Mossmanand N L Reynaert ldquoSilica induces NLRP3 inflammasomeactivation in human lung epithelial cellsrdquo Particle and FibreToxicology vol 10 no 1 article 3 2013
[83] H Watanabe O Gaide V Petrilli et al ldquoActivation of the IL-1120573-processing inflammasome is involved in contact hypersen-sitivityrdquo Journal of Investigative Dermatology vol 127 no 8 pp1956ndash1963 2007
[84] X Dai K Sayama M Tohyama et al ldquoMite allergen is adanger signal for the skin via activation of inflammasome inkeratinocytesrdquo Journal of Allergy and Clinical Immunology vol127 no 3 pp 806ndash814 2011
[85] A Varga M M Budai S Milesz A Bacsi J Tozser and SBenko ldquoRagweed pollen extract intensifies lipopolysaccharide-induced priming of NLRP3 inflammasome in humanmacrophagesrdquo Immunology vol 138 no 4 pp 392ndash4012013
[86] B Vandanmagsar Y-H Youm A Ravussin et al ldquoThe NLRP3inflammasome instigates obesity-induced inflammation andinsulin resistancerdquo Nature Medicine vol 17 no 2 pp 179ndash1892011
[87] H Wen D Gris Y Lei et al ldquoFatty acid-induced NLRP3-ASCinflammasome activation interferes with insulin signalingrdquoNature Immunology vol 12 no 5 pp 408ndash415 2011
[88] L Liang X Tan Q Zhou et al ldquoIL-1120573 triggered by pepti-doglycan and lipopolysaccharide through TLR24 and ROS-NLRP3 inflammasome- dependent pathways is involved inocular behcetrsquos diseaserdquo Investigative Ophthalmology and VisualScience vol 54 no 1 pp 402ndash414 2013
[89] S Rosengren H M Hoffman W Bugbee and D L BoyleldquoExpression and regulation of cryopyrin and related proteinsin rheumatoid arthritis synoviumrdquo Annals of the RheumaticDiseases vol 64 no 5 pp 708ndash714 2005
[90] J M Kahlenberg ldquoAnti-inflammatory panaceaThe expandingtherapeutics of interleukin-1 blockaderdquo Current Opinion inRheumatology vol 28 no 3 pp 197ndash203 2016
[91] C-H Chien M-J Lee H-C Liou H-H Liou and W-MFu ldquoLocal immunosuppressive microenvironment enhancesmigration of melanoma cells to lungs in DJ-1 knockout micerdquoPLoS ONE vol 10 no 2 Article ID e0115827 2015
[92] C Antonopoulos and G R Dubyak ldquoChemotherapy engagesmultiple pathways leading to IL-1120573 production by myeloidleukocytesrdquo OncoImmunology vol 3 no 1 Article ID e274992014
[93] E Ozaki M Campbell and S L Doyle ldquoTargeting the NLRP3inflammasome in chronic inflammatory diseases current per-spectivesrdquo Journal of Inflammation Research vol 8 pp 15ndash272015
[94] J H Hamman ldquoComposition and applications of Aloe vera leafgelrdquoMolecules vol 13 no 8 pp 1599ndash1616 2008
[95] L Langmead R J Makins and D S Rampton ldquoAnti-inflammatory effects of aloe vera gel in human colorectalmucosa in vitrordquo Alimentary Pharmacology and Therapeuticsvol 19 no 5 pp 521ndash527 2004
[96] N Yun C-H Lee and S-M Lee ldquoProtective effect of Aloe veraon polymicrobial sepsis inmicerdquo Food andChemical Toxicologyvol 47 no 6 pp 1341ndash1348 2009
[97] C S Yu F S Yu J K Chan et al ldquoAloe-emodin affects the levelsof cytokines and functions of leukocytes from Sprague-Dawleyratsrdquo In Vivo vol 20 no 4 pp 505ndash509 2006
[98] M Pulido-Moran J Moreno-Fernandez C Ramirez-Tortosaand M Ramirez-Tortosa ldquoCurcumin and healthrdquo Moleculesvol 21 no 3 article E264 2016
[99] Y-F Dong L-X Wang X Huang et al ldquoKir61 knock-down aggravates cerebral ischemiareperfusion-induced neuralinjury in micerdquo CNS Neuroscience and Therapeutics vol 19 no8 pp 617ndash624 2013
[100] P J Maier K Zemoura M A Acuna G E Yevenes HU Zeilhofer and D Benke ldquoIschemia-like oxygen and glu-cose deprivation mediates down-regulation of cell surface 120574-aminobutyric acidB receptors via the endoplasmic reticulum(ER) stress-induced transcription factor CCAATenhancer-binding protein (CEBP)-homologous protein (CHOP)rdquo TheJournal of Biological Chemistry vol 289 no 18 pp 12896ndash129072014
[101] H-Y Shin S-H Kim H-J Jeong et al ldquoEpigallocatechin-3-gallate inhibits secretion of TNF-120572 IL-6 and IL-8 through theattenuation of ERK and NF-120581B in HMC-1 cellsrdquo InternationalArchives of Allergy and Immunology vol 142 no 4 pp 335ndash3442007
[102] W P Pulskens L M Butter G J Teske et al ldquoNlrp3 preventsearly renal interstitial edema and vascular permeability inunilateral ureteral obstructionrdquo PLoS ONE vol 9 no 1 ArticleID e85775 2014
[103] S Kamath and C A Roobottom ldquoHyperdense pericardial effu-sion in dermatomyositis and contrast induced nephropathyrdquoEmergency Radiology vol 11 no 3 pp 177ndash179 2005
[104] T Akao K Kobashi and M Aburada ldquoEnzymic studies onthe animal and intestinal bacterial metabolism of geniposiderdquoBiological and Pharmaceutical Bulletin vol 17 no 12 pp 1573ndash1576 1994
[105] R Wang K C MoYung M H Zhang and K Poon ldquoUCP2-and non-UCP2-mediated electric current in eukaryotic cellsexhibits different propertiesrdquo Environmental Science and Pollu-tion Research vol 22 no 24 pp 19618ndash19631 2015
[106] J-M Lu Q Yao and C Chen ldquoGinseng compounds an updateon their molecular mechanisms and medical applicationsrdquoCurrent Vascular Pharmacology vol 7 no 3 pp 293ndash302 2009
[107] E Hernandez-Cuellar K Tsuchiya H Hara et al ldquoCuttingedge nitric oxide inhibits the NLRP3 inflammasomerdquo TheJournal of Immunology vol 189 no 11 pp 5113ndash5117 2012
[108] B B Mishra V A K Rathinam G W Martens et alldquoNitric oxide controls the immunopathology of tuberculosis byinhibiting NLRP3 inflammasome-dependent processing of IL-1120573rdquo Nature Immunology vol 14 no 1 pp 52ndash60 2013
[109] T Matsuno S-K Jung Y Matsumoto M Saito and JMorikawa ldquoPreferential cytotoxicity to tumor cells of 35-diprenyl-4-hydroxycinnamic acid (artepillin C) isolated frompropolisrdquo Anticancer Research vol 17 no 5A pp 3565ndash35681997
16 Mediators of Inflammation
[110] X Zhang J-H Zhang X-Y Chen et al ldquoReactive oxy-gen species-induced TXNIP drives fructose-mediated hepaticinflammation and lipid accumulation through NLRP3 inflam-masome activationrdquo Antioxidants and Redox Signaling vol 22no 10 pp 848ndash870 2015
[111] A Zendedel S Johann S Mehrabi et al ldquoActivation and reg-ulation of NLRP3 inflammasome by intrathecal application ofSDF-1a in a spinal cord injury modelrdquoMolecular Neurobiologyvol 53 no 5 pp 3063ndash3075 2016
[112] H Inoue and R Nakata ldquoResveratrol targets in inflammationrdquoEndocrineMetabolic and ImmuneDisordersmdashDrug Targets vol15 no 3 pp 186ndash195 2015
[113] S S Kulkarni and C Canto ldquoThe molecular targets of resver-atrolrdquo Biochimica et Biophysica Acta (BBA)mdashMolecular Basis ofDisease vol 1852 no 6 pp 1114ndash1123 2015
[114] C A Houghton R G Fassett and J S Coombes ldquoSul-foraphane translational research from laboratory bench toclinicrdquo Nutrition Reviews vol 71 no 11 pp 709ndash726 2013
[115] A T Dinkova-Kostova W D Holtzclaw R N Cole et alldquoDirect evidence that sulfhydryl groups of Keap1 are the sensorsregulating induction of phase 2 enzymes that protect againstcarcinogens and oxidantsrdquo Proceedings of the National Academyof Sciences of the United States of America vol 99 no 18 pp11908ndash11913 2002
[116] E Heiss C Herhaus K Klimo H Bartsch and C GerhauserldquoNuclear factor 120581B is a molecular target for sulforaphane-mediated anti-inflammatory mechanismsrdquo The Journal of Bio-logical Chemistry vol 276 no 34 pp 32008ndash32015 2001
[117] A Alfieri S Srivastava R C M Siow et al ldquoSulforaphanepreconditioning of the Nrf2HO-1 defense pathway protectsthe cerebral vasculature against blood-brain barrier disruptionand neurological deficits in strokerdquo Free Radical Biology andMedicine vol 65 pp 1012ndash1022 2013
[118] C Lee G H Park S-R Lee and J-H Jang ldquoAttenuation of120573 -amyloid-induced oxidative cell death by sulforaphane viaactivation of NF-E2-related factor 2rdquo Oxidative Medicine andCellular Longevity vol 2013 Article ID 313510 12 pages 2013
[119] E Barrajon-Catalan M Herranz-Lopez J Joven et al ldquoMolec-ular promiscuity of plant polyphenols in the management ofage-related diseases far beyond their antioxidant propertiesrdquoAdvances in Experimental Medicine and Biology vol 824 pp141ndash159 2014
[120] L Bravo ldquoPolyphenols chemistry dietary sources metabolismand nutritional significancerdquo Nutrition Reviews vol 56 no 11pp 317ndash333 1998
[121] D W Lamming J G Wood and D A Sinclair ldquoSmallmolecules that regulate lifespan evidence for xenohormesisrdquoMolecular Microbiology vol 53 no 4 pp 1003ndash1009 2004
[122] K T Howitz and D A Sinclair ldquoXenohormesis sensing thechemical cues of other speciesrdquo Cell vol 133 no 3 pp 387ndash3912008
[123] P L Hooper P L Hooper M Tytell and L Vıgh ldquoXeno-hormesis health benefits from an eon of plant stress responseevolutionrdquoCell Stress and Chaperones vol 15 no 6 pp 761ndash7702010
[124] B L Queen and T O Tollefsbol ldquoPolyphenols and agingrdquoCurrent Aging Science vol 3 no 1 pp 34ndash42 2010
[125] J A Baur and D A Sinclair ldquoTherapeutic potential of resvera-trol the in vivo evidencerdquo Nature Reviews Drug Discovery vol5 no 6 pp 493ndash506 2006
[126] R A Sharma A J Gescher and W P Steward ldquoCurcumin thestory so farrdquoEuropean Journal of Cancer vol 41 no 13 pp 1955ndash1968 2005
[127] K Milton ldquoMicronutrient intakes of wild primates are humansdifferentrdquo Comparative Biochemistry and Physiology Part AMolecular amp Integrative Physiology vol 136 no 1 pp 47ndash592003
turn adapting for the pursuit of longevity a theory termedas Xenohormesis [121ndash123] Interestingly the structurallyunrelated resveratrol and curcumin can achieve this caloricrestriction mimicking effect by activating AMPK and Sirt1[124] However polyphenols are also known to have anantioxidant effect activate glutathione S-transferases andinhibit COX enzymes among many other effects [125 126]Interestingly one of the most frequently used COX inhibitoris aspirin a derivative of another stress-induced phytochem-ical salicylic acid
A major concern of polyphenol use in therapy is thebioavailability of these compounds Nevertheless typicaldietary polyphenol intake is about 14mgkgday which iswithin the range of providing biologically active doses [127]
6 Concluding Remarks
Most of the time inflammasome-mediated IL-1120573 productionor caspase-mediated pyroptosis is beneficial for the host as itprotects from infection or prevents further damageHoweverprolonged cytokine production as in the case of sterileinflammation caused by endogenous danger signals maylead to the development of autoinflammatory or metabolicdiseases Chronic inflammation compromises the hostrsquos lifequality and requires sustained pharmacological and surgicaltreatments The paradigm of drug discovery in Westernmedicine is to develop highly selective compounds againstindividual druggable targets Currently the main treatmentmethods for these patients are targeting IL-1120573 Howeverprolonged usage of drugs may induce different side effectsfurthermore some form of medications are very expensivewhich limits their widespread use
Besides the high expenses another drawback of tradi-tional drug design is that many of the promising compoundsfail in the early or later stages of drug development Tradi-tional medicine uses many plant products to treat diseaseshowever the exact mechanisms behind their use is stillmostly lacking partially as a consequence of the pleiotropiceffect of the active compounds as detailed in this reviewNevertheless clarification of the molecular mechanism ofaction of such natural compounds already used in traditionalmedicine for quite some time will undoubtedly aid in theproduction of safe and cheap candidate medications to beused in the treatment of diseases including those appearingas a consequence of NLRP3 inflammasome-mediated IL-1120573overproduction
Competing Interests
The authors declare no conflict of interests
Acknowledgments
This work was supported by OTKA-K 109429 Szilvia Benkois a receiver of Lajos Szodoray Postdoctoral Fellowship andJanos Bolyai Postdoctoral Fellowship
References
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[46] T Ichinohe T Yamazaki T Koshiba and Y Yanagi ldquoMitochon-drial protein mitofusin 2 is required for NLRP3 inflammasomeactivation afterRNAvirus infectionrdquoProceedings of theNationalAcademy of Sciences of the United States of America vol 110 no44 pp 17963ndash17968 2013
[47] N Subramanian K Natarajan M R Clatworthy Z Wangand R N Germain ldquoThe adaptor MAVS promotes NLRP3mitochondrial localization and inflammasome activationrdquo Cellvol 153 no 2 pp 348ndash361 2013
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14 Mediators of Inflammation
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[50] T Misawa M Takahama T Kozaki et al ldquoMicrotubule-drivenspatial arrangement ofmitochondria promotes activation of theNLRP3 inflammasomerdquo Nature Immunology vol 14 no 5 pp454ndash460 2013
[51] M M Budai A Varga S Milesz J Tozser and S BenkoldquoAloe vera downregulates LPS-induced inflammatory cytokineproduction and expression of NLRP3 inflammasome in humanmacrophagesrdquo Molecular Immunology vol 56 no 4 pp 471ndash479 2013
[52] J-W Han D-W Shim W-Y Shin et al ldquoAnti-inflammatoryeffect of emodin via attenuation of NLRP3 inflammasomeactivationrdquo International Journal of Molecular Sciences vol 16no 4 pp 8102ndash8109 2015
[53] Y Li J Li S Li et al ldquoCurcumin attenuates glutamate neurotox-icity in the hippocampus by suppression of ER stress-associatedTXNIPNLRP3 inflammasome activation in a manner depen-dent onAMPKrdquoToxicology andApplied Pharmacology vol 286no 1 pp 53ndash63 2015
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[56] Z Gao Y Han Y Hu et al ldquoTargeting HO-1 byepigallocatechin-3-gallate reduces contrast-induced renalinjury via anti-oxidative stress and anti-inflammationpathwaysrdquo PLOS ONE vol 11 no 2 article e0149032 2016
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[62] C-W Pan Z-Z Pan J-J Hu et al ldquoMangiferin alleviateslipopolysaccharide and D-galactosamine-induced acute liverinjury by activating the Nrf2 pathway and inhibiting NLRP3inflammasome activationrdquo European Journal of Pharmacologyvol 770 pp 85ndash91 2016
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[64] C Wang Y Pan Q-Y Zhang F-M Wang and L-D KongldquoQuercetin and allopurinol ameliorate kidney injury in STZ-treated rats with regulation of renal NLRP3 inflammasomeactivation and lipid accumulationrdquo PLoS ONE vol 7 no 6Article ID e38285 2012
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[67] Q-Y Zhang Y Pan R Wang et al ldquoQuercetin inhibitsAMPKTXNIP activation and reduces inflammatory lesions toimprove insulin signaling defect in the hypothalamus of highfructose-fed ratsrdquo Journal of Nutritional Biochemistry vol 25no 4 pp 420ndash428 2014
[68] J Wu X Xu Y Li et al ldquoQuercetin luteolin and epigallo-catechin gallate alleviate TXNIP and NLRP3-mediated inflam-mation and apoptosis with regulation of AMPK in endothelialcellsrdquo European Journal of Pharmacology vol 745 pp 59ndash682015
[69] W Jiang Y Huang N Han et al ldquoQuercetin suppresses NLRP3inflammasome activation and attenuates histopathology in a ratmodel of spinal cord injuryrdquo Spinal Cord vol 54 pp 592ndash5962016
[70] Y Fu Y Wang L Du et al ldquoResveratrol inhibits ionisingirradiation-induced inflammation in MSCs by activating Sirt1and limiting NLRP-3 inflammasome activationrdquo InternationalJournal ofMolecular Sciences vol 14 no 7 pp 14105ndash14118 2013
[71] T-T Huang H-C Lai Y-B Chen et al ldquoCis-Resveratrolproduces anti-inflammatory effects by inhibiting canonicaland non-canonical inflammasomes in macrophagesrdquo InnateImmunity vol 20 no 7 pp 735ndash750 2014
[72] Y-P Chang S-M Ka W-H Hsu et al ldquoResveratrol inhibitsNLRP3 inflammasome activation by preserving mitochondrialintegrity and augmenting autophagyrdquo Journal of Cellular Physi-ology vol 230 no 7 pp 1567ndash1579 2015
[73] S J Yang and Y Lim ldquoResveratrol ameliorates hepaticmetaflammation and inhibits NLRP3 inflammasome activa-tionrdquoMetabolism vol 63 no 5 pp 693ndash701 2014
[74] D-M Sui Q Xie W-J Yi et al ldquoResveratrol protects againstsepsis-associated encephalopathy and inhibits the NLRP3IL-1 120573 axis in microgliardquo Mediators of Inflammation vol 2016Article ID 1045657 10 pages 2016
[75] J Wu X Li G Zhu Y Zhang M He and J Zhang ldquoTherole of Resveratrol-inducedmitophagyautophagy in peritonealmesothelial cells inflammatory injury via NLRP3 inflamma-some activation triggered bymitochondrial ROSrdquoExperimentalCell Research vol 341 no 1 pp 42ndash53 2016
[76] Y W An K A Jhang S Y Woo J L Kang and Y HChong ldquoSulforaphane exerts its anti-inflammatory effectagainst amyloid-120573 peptide via STAT-1 dephosphorylationand activation of Nrf2HO-1 cascade in human THP-1macrophagesrdquo Neurobiology of Aging vol 38 pp 1ndash10 2016
[77] G Yang H E Lee and J Y Lee ldquoA pharmacological inhibitorof NLRP3 inflammasome prevents non-alcoholic fatty liver
Mediators of Inflammation 15
disease in a mouse model induced by high fat dietrdquo ScientificReports vol 6 Article ID 24399 2016
[78] L Franchi R Munoz-Planillo and G Nunez ldquoSensing andreacting to microbes through the inflammasomesrdquo NatureImmunology vol 13 no 4 pp 325ndash332 2012
[79] S L Cassel and F S Sutterwala ldquoSterile inflammatory responsesmediated by the NLRP3 inflammasomerdquo European Journal ofImmunology vol 40 no 3 pp 607ndash611 2010
[80] M-S Tan J-T Yu T Jiang X-C Zhu and L Tan ldquoThe NLRP3inflammasome in alzheimerrsquos diseaserdquoMolecular Neurobiologyvol 48 no 3 pp 875ndash882 2013
[81] M Gold and J El Khoury ldquo120573-amyloid microglia andthe inflammasome in Alzheimerrsquos diseaserdquo Seminars inImmunopathology vol 37 no 6 pp 607ndash611 2015
[82] P M Peeters T N Perkins E F M Wouters B T Mossmanand N L Reynaert ldquoSilica induces NLRP3 inflammasomeactivation in human lung epithelial cellsrdquo Particle and FibreToxicology vol 10 no 1 article 3 2013
[83] H Watanabe O Gaide V Petrilli et al ldquoActivation of the IL-1120573-processing inflammasome is involved in contact hypersen-sitivityrdquo Journal of Investigative Dermatology vol 127 no 8 pp1956ndash1963 2007
[84] X Dai K Sayama M Tohyama et al ldquoMite allergen is adanger signal for the skin via activation of inflammasome inkeratinocytesrdquo Journal of Allergy and Clinical Immunology vol127 no 3 pp 806ndash814 2011
[85] A Varga M M Budai S Milesz A Bacsi J Tozser and SBenko ldquoRagweed pollen extract intensifies lipopolysaccharide-induced priming of NLRP3 inflammasome in humanmacrophagesrdquo Immunology vol 138 no 4 pp 392ndash4012013
[86] B Vandanmagsar Y-H Youm A Ravussin et al ldquoThe NLRP3inflammasome instigates obesity-induced inflammation andinsulin resistancerdquo Nature Medicine vol 17 no 2 pp 179ndash1892011
[87] H Wen D Gris Y Lei et al ldquoFatty acid-induced NLRP3-ASCinflammasome activation interferes with insulin signalingrdquoNature Immunology vol 12 no 5 pp 408ndash415 2011
[88] L Liang X Tan Q Zhou et al ldquoIL-1120573 triggered by pepti-doglycan and lipopolysaccharide through TLR24 and ROS-NLRP3 inflammasome- dependent pathways is involved inocular behcetrsquos diseaserdquo Investigative Ophthalmology and VisualScience vol 54 no 1 pp 402ndash414 2013
[89] S Rosengren H M Hoffman W Bugbee and D L BoyleldquoExpression and regulation of cryopyrin and related proteinsin rheumatoid arthritis synoviumrdquo Annals of the RheumaticDiseases vol 64 no 5 pp 708ndash714 2005
[90] J M Kahlenberg ldquoAnti-inflammatory panaceaThe expandingtherapeutics of interleukin-1 blockaderdquo Current Opinion inRheumatology vol 28 no 3 pp 197ndash203 2016
[91] C-H Chien M-J Lee H-C Liou H-H Liou and W-MFu ldquoLocal immunosuppressive microenvironment enhancesmigration of melanoma cells to lungs in DJ-1 knockout micerdquoPLoS ONE vol 10 no 2 Article ID e0115827 2015
[92] C Antonopoulos and G R Dubyak ldquoChemotherapy engagesmultiple pathways leading to IL-1120573 production by myeloidleukocytesrdquo OncoImmunology vol 3 no 1 Article ID e274992014
[93] E Ozaki M Campbell and S L Doyle ldquoTargeting the NLRP3inflammasome in chronic inflammatory diseases current per-spectivesrdquo Journal of Inflammation Research vol 8 pp 15ndash272015
[94] J H Hamman ldquoComposition and applications of Aloe vera leafgelrdquoMolecules vol 13 no 8 pp 1599ndash1616 2008
[95] L Langmead R J Makins and D S Rampton ldquoAnti-inflammatory effects of aloe vera gel in human colorectalmucosa in vitrordquo Alimentary Pharmacology and Therapeuticsvol 19 no 5 pp 521ndash527 2004
[96] N Yun C-H Lee and S-M Lee ldquoProtective effect of Aloe veraon polymicrobial sepsis inmicerdquo Food andChemical Toxicologyvol 47 no 6 pp 1341ndash1348 2009
[97] C S Yu F S Yu J K Chan et al ldquoAloe-emodin affects the levelsof cytokines and functions of leukocytes from Sprague-Dawleyratsrdquo In Vivo vol 20 no 4 pp 505ndash509 2006
[98] M Pulido-Moran J Moreno-Fernandez C Ramirez-Tortosaand M Ramirez-Tortosa ldquoCurcumin and healthrdquo Moleculesvol 21 no 3 article E264 2016
[99] Y-F Dong L-X Wang X Huang et al ldquoKir61 knock-down aggravates cerebral ischemiareperfusion-induced neuralinjury in micerdquo CNS Neuroscience and Therapeutics vol 19 no8 pp 617ndash624 2013
[100] P J Maier K Zemoura M A Acuna G E Yevenes HU Zeilhofer and D Benke ldquoIschemia-like oxygen and glu-cose deprivation mediates down-regulation of cell surface 120574-aminobutyric acidB receptors via the endoplasmic reticulum(ER) stress-induced transcription factor CCAATenhancer-binding protein (CEBP)-homologous protein (CHOP)rdquo TheJournal of Biological Chemistry vol 289 no 18 pp 12896ndash129072014
[101] H-Y Shin S-H Kim H-J Jeong et al ldquoEpigallocatechin-3-gallate inhibits secretion of TNF-120572 IL-6 and IL-8 through theattenuation of ERK and NF-120581B in HMC-1 cellsrdquo InternationalArchives of Allergy and Immunology vol 142 no 4 pp 335ndash3442007
[102] W P Pulskens L M Butter G J Teske et al ldquoNlrp3 preventsearly renal interstitial edema and vascular permeability inunilateral ureteral obstructionrdquo PLoS ONE vol 9 no 1 ArticleID e85775 2014
[103] S Kamath and C A Roobottom ldquoHyperdense pericardial effu-sion in dermatomyositis and contrast induced nephropathyrdquoEmergency Radiology vol 11 no 3 pp 177ndash179 2005
[104] T Akao K Kobashi and M Aburada ldquoEnzymic studies onthe animal and intestinal bacterial metabolism of geniposiderdquoBiological and Pharmaceutical Bulletin vol 17 no 12 pp 1573ndash1576 1994
[105] R Wang K C MoYung M H Zhang and K Poon ldquoUCP2-and non-UCP2-mediated electric current in eukaryotic cellsexhibits different propertiesrdquo Environmental Science and Pollu-tion Research vol 22 no 24 pp 19618ndash19631 2015
[106] J-M Lu Q Yao and C Chen ldquoGinseng compounds an updateon their molecular mechanisms and medical applicationsrdquoCurrent Vascular Pharmacology vol 7 no 3 pp 293ndash302 2009
[107] E Hernandez-Cuellar K Tsuchiya H Hara et al ldquoCuttingedge nitric oxide inhibits the NLRP3 inflammasomerdquo TheJournal of Immunology vol 189 no 11 pp 5113ndash5117 2012
[108] B B Mishra V A K Rathinam G W Martens et alldquoNitric oxide controls the immunopathology of tuberculosis byinhibiting NLRP3 inflammasome-dependent processing of IL-1120573rdquo Nature Immunology vol 14 no 1 pp 52ndash60 2013
[109] T Matsuno S-K Jung Y Matsumoto M Saito and JMorikawa ldquoPreferential cytotoxicity to tumor cells of 35-diprenyl-4-hydroxycinnamic acid (artepillin C) isolated frompropolisrdquo Anticancer Research vol 17 no 5A pp 3565ndash35681997
16 Mediators of Inflammation
[110] X Zhang J-H Zhang X-Y Chen et al ldquoReactive oxy-gen species-induced TXNIP drives fructose-mediated hepaticinflammation and lipid accumulation through NLRP3 inflam-masome activationrdquo Antioxidants and Redox Signaling vol 22no 10 pp 848ndash870 2015
[111] A Zendedel S Johann S Mehrabi et al ldquoActivation and reg-ulation of NLRP3 inflammasome by intrathecal application ofSDF-1a in a spinal cord injury modelrdquoMolecular Neurobiologyvol 53 no 5 pp 3063ndash3075 2016
[112] H Inoue and R Nakata ldquoResveratrol targets in inflammationrdquoEndocrineMetabolic and ImmuneDisordersmdashDrug Targets vol15 no 3 pp 186ndash195 2015
[113] S S Kulkarni and C Canto ldquoThe molecular targets of resver-atrolrdquo Biochimica et Biophysica Acta (BBA)mdashMolecular Basis ofDisease vol 1852 no 6 pp 1114ndash1123 2015
[114] C A Houghton R G Fassett and J S Coombes ldquoSul-foraphane translational research from laboratory bench toclinicrdquo Nutrition Reviews vol 71 no 11 pp 709ndash726 2013
[115] A T Dinkova-Kostova W D Holtzclaw R N Cole et alldquoDirect evidence that sulfhydryl groups of Keap1 are the sensorsregulating induction of phase 2 enzymes that protect againstcarcinogens and oxidantsrdquo Proceedings of the National Academyof Sciences of the United States of America vol 99 no 18 pp11908ndash11913 2002
[116] E Heiss C Herhaus K Klimo H Bartsch and C GerhauserldquoNuclear factor 120581B is a molecular target for sulforaphane-mediated anti-inflammatory mechanismsrdquo The Journal of Bio-logical Chemistry vol 276 no 34 pp 32008ndash32015 2001
[117] A Alfieri S Srivastava R C M Siow et al ldquoSulforaphanepreconditioning of the Nrf2HO-1 defense pathway protectsthe cerebral vasculature against blood-brain barrier disruptionand neurological deficits in strokerdquo Free Radical Biology andMedicine vol 65 pp 1012ndash1022 2013
[118] C Lee G H Park S-R Lee and J-H Jang ldquoAttenuation of120573 -amyloid-induced oxidative cell death by sulforaphane viaactivation of NF-E2-related factor 2rdquo Oxidative Medicine andCellular Longevity vol 2013 Article ID 313510 12 pages 2013
[119] E Barrajon-Catalan M Herranz-Lopez J Joven et al ldquoMolec-ular promiscuity of plant polyphenols in the management ofage-related diseases far beyond their antioxidant propertiesrdquoAdvances in Experimental Medicine and Biology vol 824 pp141ndash159 2014
[120] L Bravo ldquoPolyphenols chemistry dietary sources metabolismand nutritional significancerdquo Nutrition Reviews vol 56 no 11pp 317ndash333 1998
[121] D W Lamming J G Wood and D A Sinclair ldquoSmallmolecules that regulate lifespan evidence for xenohormesisrdquoMolecular Microbiology vol 53 no 4 pp 1003ndash1009 2004
[122] K T Howitz and D A Sinclair ldquoXenohormesis sensing thechemical cues of other speciesrdquo Cell vol 133 no 3 pp 387ndash3912008
[123] P L Hooper P L Hooper M Tytell and L Vıgh ldquoXeno-hormesis health benefits from an eon of plant stress responseevolutionrdquoCell Stress and Chaperones vol 15 no 6 pp 761ndash7702010
[124] B L Queen and T O Tollefsbol ldquoPolyphenols and agingrdquoCurrent Aging Science vol 3 no 1 pp 34ndash42 2010
[125] J A Baur and D A Sinclair ldquoTherapeutic potential of resvera-trol the in vivo evidencerdquo Nature Reviews Drug Discovery vol5 no 6 pp 493ndash506 2006
[126] R A Sharma A J Gescher and W P Steward ldquoCurcumin thestory so farrdquoEuropean Journal of Cancer vol 41 no 13 pp 1955ndash1968 2005
[127] K Milton ldquoMicronutrient intakes of wild primates are humansdifferentrdquo Comparative Biochemistry and Physiology Part AMolecular amp Integrative Physiology vol 136 no 1 pp 47ndash592003
[17] A Halle V Hornung G C Petzold et al ldquoThe NALP3inflammasome is involved in the innate immune response toamyloid-120573rdquoNature Immunology vol 9 no 8 pp 857ndash865 2008
[18] B Pazar H-K Ea S Narayan et al ldquoBasic calcium phosphatecrystals induce monocytemacrophage IL-1120573 secretion throughthe NLRP3 inflammasome in vitrordquo Journal of Immunology vol186 no 4 pp 2495ndash2502 2011
[19] P Duewell H Kono K J Rayner et al ldquoNLRP3 inflammasomesare required for atherogenesis and activated by cholesterolcrystalsrdquo Nature vol 464 no 7293 pp 1357ndash1361 2010
[20] S Benko D J Philpott and S E Girardin ldquoThe microbial anddanger signals that activate Nod-like receptorsrdquo Cytokine vol43 no 3 pp 368ndash373 2008
[21] F G Bauernfeind G Horvath A Stutz et al ldquoCutting edgeNF-120581B activating pattern recognition and cytokine receptorslicense NLRP3 inflammasome activation by regulating NLRP3expressionrdquo Journal of Immunology vol 183 no 2 pp 787ndash7912009
[22] M G Ghonime O R Shamaa S Das et al ldquoInflammasomepriming by lipopolysaccharide is dependent upon ERK signal-ing and proteasome functionrdquo Journal of Immunology vol 192no 8 pp 3881ndash3888 2014
[23] Q He H You X-M Li T-H Liu P Wang and B-E WangldquoHMGB1 promotes the synthesis of pro-il-1120573 and pro-il-18by activation of p38 MAPK and NF-kB through receptorsfor advanced glycation end-products in macrophagesrdquo AsianPacific Journal of Cancer Prevention vol 13 no 4 pp 1365ndash13702012
[24] C Jin and R A Flavell ldquoMolecular mechanism of NLRP3inflammasome activationrdquo Journal of Clinical Immunology vol30 no 5 pp 628ndash631 2010
[25] S MMan and T-D Kanneganti ldquoRegulation of inflammasomeactivationrdquo Immunological Reviews vol 265 no 1 pp 6ndash212015
[26] K Shimada T R Crother J Karlin et al ldquoOxidized mito-chondrial DNA activates the NLRP3 inflammasome duringapoptosisrdquo Immunity vol 36 no 3 pp 401ndash414 2012
[27] G-S Lee N Subramanian A I Kim et al ldquoThe calcium-sensing receptor regulates the NLRP3 inflammasome throughCa2+ and cAMPrdquo Nature vol 491 no 7427 pp 123ndash127 2012
[28] A J Greaney SH Leppla andMMoayeri ldquoBacterial exotoxinsand the inflammasomerdquo Frontiers in Immunology vol 6 article570 2015
[29] E I Elliott and F S Sutterwala ldquoInitiation and perpetuation ofNLRP3 inflammasome activation and assemblyrdquo ImmunologicalReviews vol 265 no 1 pp 35ndash52 2015
[30] A Sokolovska C E Becker W K E Ip et al ldquoActiva-tion of caspase-1 by the NLRP3 inflammasome regulates theNADPHoxidaseNOX2 to control phagosome functionrdquoNatureImmunology vol 14 no 6 pp 543ndash553 2013
[31] S Kim Y Joe S O Jeong et al ldquoEndoplasmic reticulum stressis sufficient for the induction of IL-1120573 production via activationof the NF-120581B and inflammasome pathwaysrdquo Innate Immunityvol 20 no 8 pp 799ndash815 2014
[32] A G Lerner J-P Upton P V K Praveen et al ldquoIRE1120572induces thioredoxin-interacting protein to activate the NLRP3inflammasome and promote programmed cell death underirremediable ER stressrdquo Cell Metabolism vol 16 no 2 pp 250ndash264 2012
[33] S Freigang F Ampenberger G Spohn et al ldquoNrf2 is essentialfor cholesterol crystal-induced inflammasome activation and
exacerbation of atherosclerosisrdquo European Journal of Immunol-ogy vol 41 no 7 pp 2040ndash2051 2011
[34] G M Tannahill and L A J OrsquoNeill ldquoThe emerging role ofmetabolic regulation in the functioning of Toll-like receptorsand the NOD-like receptor Nlrp3rdquo FEBS Letters vol 585 no11 pp 1568ndash1572 2011
[35] M Haneklaus and L A J OrsquoNeill ldquoNLRP3 at the interfaceof metabolism and inflammationrdquo Immunological Reviews vol265 no 1 pp 53ndash62 2015
[36] F Bauernfeind E Bartok A Rieger L Franchi G Nunez andV Hornung ldquoCutting edge reactive oxygen species inhibitorsblock priming but not activation of the NLRP3 inflamma-somerdquo The Journal of Immunology vol 187 no 2 pp 613ndash6172011
[37] D Perregaux and C A Gabel ldquoInterleukin-1 beta maturationand release in response to ATP and nigericin Evidence thatpotassium depletion mediated by these agents is a necessaryand common feature of their activityrdquoThe Journal of BiologicalChemistry vol 269 no 21 pp 15195ndash15203 1994
[38] J M Kahlenberg K C Lundberg S B Kertesy Y Qu and GR Dubyak ldquoPotentiation of caspase-1 activation by the P2X7receptor is dependent on TLR signals and requires NF-120581B-driven protein synthesisrdquo Journal of Immunology vol 175 no11 pp 7611ndash7622 2005
[39] R Munoz-Planillo P Kuffa G Martınez-Colon B Smith TRajendiran and G Nunez ldquoK+ efflux is the common triggerof NLRP3 inflammasome activation by bacterial toxins andparticulate matterrdquo Immunity vol 38 no 6 pp 1142ndash1153 2013
[40] V Petrilli S Papin C Dostert A Mayor F Martinon and JTschopp ldquoActivation of the NALP3 inflammasome is triggeredby low intracellular potassium concentrationrdquo Cell Death andDifferentiation vol 14 no 9 pp 1583ndash1589 2007
[41] T Murakami J Ockinger J Yu et al ldquoCritical role for calciummobilization in activation of the NLRP3 inflammasomerdquo Pro-ceedings of the National Academy of Sciences of the United Statesof America vol 109 no 28 pp 11282ndash11287 2012
[42] V Hornung F Bauernfeind A Halle et al ldquoSilica crystals andaluminum salts activate the NALP3 inflammasome throughphagosomal destabilizationrdquo Nature Immunology vol 9 no 8pp 847ndash856 2008
[43] J Dan Dunn L A J Alvarez X Zhang and T SoldatildquoReactive oxygen species and mitochondria a nexus of cellularhomeostasisrdquo Redox Biology vol 6 pp 472ndash485 2015
[44] S S Iyer Q He J R Janczy et al ldquoMitochondrial cardiolipinis required for Nlrp3 inflammasome activationrdquo Immunity vol39 no 2 pp 311ndash323 2013
[45] X Wang W Jiang Y Yan et al ldquoRNA viruses promoteactivation of the NLRP3 inflammasome through a RIP1-RIP3-DRP1 signaling pathwayrdquoNature Immunology vol 15 no 12 pp1126ndash1133 2014
[46] T Ichinohe T Yamazaki T Koshiba and Y Yanagi ldquoMitochon-drial protein mitofusin 2 is required for NLRP3 inflammasomeactivation afterRNAvirus infectionrdquoProceedings of theNationalAcademy of Sciences of the United States of America vol 110 no44 pp 17963ndash17968 2013
[47] N Subramanian K Natarajan M R Clatworthy Z Wangand R N Germain ldquoThe adaptor MAVS promotes NLRP3mitochondrial localization and inflammasome activationrdquo Cellvol 153 no 2 pp 348ndash361 2013
[48] S Y Shaw K Tran A B Castoreno et al ldquoSelective modulationof autophagy innate immunity and adaptive immunity by small
14 Mediators of Inflammation
moleculesrdquo ACS Chemical Biology vol 8 no 12 pp 2724ndash27332013
[49] K Nakahira J A Haspel V A K Rathinam et al ldquoAutophagyproteins regulate innate immune responses by inhibiting therelease of mitochondrial DNA mediated by the NALP3 inflam-masomerdquo Nature Immunology vol 12 no 3 pp 222ndash230 2011
[50] T Misawa M Takahama T Kozaki et al ldquoMicrotubule-drivenspatial arrangement ofmitochondria promotes activation of theNLRP3 inflammasomerdquo Nature Immunology vol 14 no 5 pp454ndash460 2013
[51] M M Budai A Varga S Milesz J Tozser and S BenkoldquoAloe vera downregulates LPS-induced inflammatory cytokineproduction and expression of NLRP3 inflammasome in humanmacrophagesrdquo Molecular Immunology vol 56 no 4 pp 471ndash479 2013
[52] J-W Han D-W Shim W-Y Shin et al ldquoAnti-inflammatoryeffect of emodin via attenuation of NLRP3 inflammasomeactivationrdquo International Journal of Molecular Sciences vol 16no 4 pp 8102ndash8109 2015
[53] Y Li J Li S Li et al ldquoCurcumin attenuates glutamate neurotox-icity in the hippocampus by suppression of ER stress-associatedTXNIPNLRP3 inflammasome activation in a manner depen-dent onAMPKrdquoToxicology andApplied Pharmacology vol 286no 1 pp 53ndash63 2015
[54] Z Gong J Zhou H Li et al ldquoCurcumin suppresses NLRP3inflammasome activation and protects against LPS-inducedseptic shockrdquo Molecular Nutrition and Food Research vol 59no 11 pp 2132ndash2142 2015
[55] P-Y Tsai S-M Ka J-M Chang et al ldquoEpigallocatechin-3-gallate prevents lupus nephritis development in mice viaenhancing the Nrf2 antioxidant pathway and inhibiting NLRP3inflammasome activationrdquo Free Radical Biology and Medicinevol 51 no 3 pp 744ndash754 2011
[56] Z Gao Y Han Y Hu et al ldquoTargeting HO-1 byepigallocatechin-3-gallate reduces contrast-induced renalinjury via anti-oxidative stress and anti-inflammationpathwaysrdquo PLOS ONE vol 11 no 2 article e0149032 2016
[57] V Rajanbabu L Galam J Fukumoto et al ldquoGenipin suppressesNLRP3 inflammasome activation through uncoupling protein-2rdquo Cellular Immunology vol 297 no 1 pp 40ndash45 2015
[58] S-X Yu C-T DuW Chen et al ldquoGenipin inhibits NLRP3 andNLRC4 inflammasome activation via autophagy suppressionrdquoScientific Reports vol 5 article 17935 2015
[59] J Kim H Ahn B-C Han et al ldquoKorean red ginseng extractsinhibit NLRP3 and AIM2 inflammasome activationrdquo Immunol-ogy Letters vol 158 no 1-2 pp 143ndash150 2014
[60] S-J Yoon J-Y Park S Choi et al ldquoGinsenoside Rg3 regulatesS-nitrosylation of the NLRP3 inflammasome via suppression ofiNOSrdquo Biochemical and Biophysical Research Communicationsvol 463 no 4 pp 1184ndash1189 2015
[61] J Song J Li F Hou X Wang and B Liu ldquoMangiferininhibits endoplasmic reticulum stress-associated thioredoxin-interacting proteinNLRP3 inflammasome activation with reg-ulation of AMPK in endothelial cellsrdquo Metabolism vol 64 no3 pp 428ndash437 2015
[62] C-W Pan Z-Z Pan J-J Hu et al ldquoMangiferin alleviateslipopolysaccharide and D-galactosamine-induced acute liverinjury by activating the Nrf2 pathway and inhibiting NLRP3inflammasome activationrdquo European Journal of Pharmacologyvol 770 pp 85ndash91 2016
[63] J I Hori D S Zamboni D B Carrao GHGoldman andAABerretta ldquoThe inhibition of inflammasome by Brazilian propo-lis (EPP-AF)rdquo Evidence-Based Complementary and AlternativeMedicine vol 2013 Article ID 418508 11 pages 2013
[64] C Wang Y Pan Q-Y Zhang F-M Wang and L-D KongldquoQuercetin and allopurinol ameliorate kidney injury in STZ-treated rats with regulation of renal NLRP3 inflammasomeactivation and lipid accumulationrdquo PLoS ONE vol 7 no 6Article ID e38285 2012
[65] Q-H Hu X Zhang Y Pan Y-C Li and L-D Kong ldquoAllop-urinol quercetin and rutin ameliorate renal NLRP3 inflamma-some activation and lipid accumulation in fructose-fed ratsrdquoBiochemical Pharmacology vol 84 no 1 pp 113ndash125 2012
[66] WWangCWangX-QDing et al ldquoQuercetin and allopurinolreduce liver thioredoxin-interacting protein to alleviate inflam-mation and lipid accumulation in diabetic ratsrdquo British Journalof Pharmacology vol 169 no 6 pp 1352ndash1371 2013
[67] Q-Y Zhang Y Pan R Wang et al ldquoQuercetin inhibitsAMPKTXNIP activation and reduces inflammatory lesions toimprove insulin signaling defect in the hypothalamus of highfructose-fed ratsrdquo Journal of Nutritional Biochemistry vol 25no 4 pp 420ndash428 2014
[68] J Wu X Xu Y Li et al ldquoQuercetin luteolin and epigallo-catechin gallate alleviate TXNIP and NLRP3-mediated inflam-mation and apoptosis with regulation of AMPK in endothelialcellsrdquo European Journal of Pharmacology vol 745 pp 59ndash682015
[69] W Jiang Y Huang N Han et al ldquoQuercetin suppresses NLRP3inflammasome activation and attenuates histopathology in a ratmodel of spinal cord injuryrdquo Spinal Cord vol 54 pp 592ndash5962016
[70] Y Fu Y Wang L Du et al ldquoResveratrol inhibits ionisingirradiation-induced inflammation in MSCs by activating Sirt1and limiting NLRP-3 inflammasome activationrdquo InternationalJournal ofMolecular Sciences vol 14 no 7 pp 14105ndash14118 2013
[71] T-T Huang H-C Lai Y-B Chen et al ldquoCis-Resveratrolproduces anti-inflammatory effects by inhibiting canonicaland non-canonical inflammasomes in macrophagesrdquo InnateImmunity vol 20 no 7 pp 735ndash750 2014
[72] Y-P Chang S-M Ka W-H Hsu et al ldquoResveratrol inhibitsNLRP3 inflammasome activation by preserving mitochondrialintegrity and augmenting autophagyrdquo Journal of Cellular Physi-ology vol 230 no 7 pp 1567ndash1579 2015
[73] S J Yang and Y Lim ldquoResveratrol ameliorates hepaticmetaflammation and inhibits NLRP3 inflammasome activa-tionrdquoMetabolism vol 63 no 5 pp 693ndash701 2014
[74] D-M Sui Q Xie W-J Yi et al ldquoResveratrol protects againstsepsis-associated encephalopathy and inhibits the NLRP3IL-1 120573 axis in microgliardquo Mediators of Inflammation vol 2016Article ID 1045657 10 pages 2016
[75] J Wu X Li G Zhu Y Zhang M He and J Zhang ldquoTherole of Resveratrol-inducedmitophagyautophagy in peritonealmesothelial cells inflammatory injury via NLRP3 inflamma-some activation triggered bymitochondrial ROSrdquoExperimentalCell Research vol 341 no 1 pp 42ndash53 2016
[76] Y W An K A Jhang S Y Woo J L Kang and Y HChong ldquoSulforaphane exerts its anti-inflammatory effectagainst amyloid-120573 peptide via STAT-1 dephosphorylationand activation of Nrf2HO-1 cascade in human THP-1macrophagesrdquo Neurobiology of Aging vol 38 pp 1ndash10 2016
[77] G Yang H E Lee and J Y Lee ldquoA pharmacological inhibitorof NLRP3 inflammasome prevents non-alcoholic fatty liver
Mediators of Inflammation 15
disease in a mouse model induced by high fat dietrdquo ScientificReports vol 6 Article ID 24399 2016
[78] L Franchi R Munoz-Planillo and G Nunez ldquoSensing andreacting to microbes through the inflammasomesrdquo NatureImmunology vol 13 no 4 pp 325ndash332 2012
[79] S L Cassel and F S Sutterwala ldquoSterile inflammatory responsesmediated by the NLRP3 inflammasomerdquo European Journal ofImmunology vol 40 no 3 pp 607ndash611 2010
[80] M-S Tan J-T Yu T Jiang X-C Zhu and L Tan ldquoThe NLRP3inflammasome in alzheimerrsquos diseaserdquoMolecular Neurobiologyvol 48 no 3 pp 875ndash882 2013
[81] M Gold and J El Khoury ldquo120573-amyloid microglia andthe inflammasome in Alzheimerrsquos diseaserdquo Seminars inImmunopathology vol 37 no 6 pp 607ndash611 2015
[82] P M Peeters T N Perkins E F M Wouters B T Mossmanand N L Reynaert ldquoSilica induces NLRP3 inflammasomeactivation in human lung epithelial cellsrdquo Particle and FibreToxicology vol 10 no 1 article 3 2013
[83] H Watanabe O Gaide V Petrilli et al ldquoActivation of the IL-1120573-processing inflammasome is involved in contact hypersen-sitivityrdquo Journal of Investigative Dermatology vol 127 no 8 pp1956ndash1963 2007
[84] X Dai K Sayama M Tohyama et al ldquoMite allergen is adanger signal for the skin via activation of inflammasome inkeratinocytesrdquo Journal of Allergy and Clinical Immunology vol127 no 3 pp 806ndash814 2011
[85] A Varga M M Budai S Milesz A Bacsi J Tozser and SBenko ldquoRagweed pollen extract intensifies lipopolysaccharide-induced priming of NLRP3 inflammasome in humanmacrophagesrdquo Immunology vol 138 no 4 pp 392ndash4012013
[86] B Vandanmagsar Y-H Youm A Ravussin et al ldquoThe NLRP3inflammasome instigates obesity-induced inflammation andinsulin resistancerdquo Nature Medicine vol 17 no 2 pp 179ndash1892011
[87] H Wen D Gris Y Lei et al ldquoFatty acid-induced NLRP3-ASCinflammasome activation interferes with insulin signalingrdquoNature Immunology vol 12 no 5 pp 408ndash415 2011
[88] L Liang X Tan Q Zhou et al ldquoIL-1120573 triggered by pepti-doglycan and lipopolysaccharide through TLR24 and ROS-NLRP3 inflammasome- dependent pathways is involved inocular behcetrsquos diseaserdquo Investigative Ophthalmology and VisualScience vol 54 no 1 pp 402ndash414 2013
[89] S Rosengren H M Hoffman W Bugbee and D L BoyleldquoExpression and regulation of cryopyrin and related proteinsin rheumatoid arthritis synoviumrdquo Annals of the RheumaticDiseases vol 64 no 5 pp 708ndash714 2005
[90] J M Kahlenberg ldquoAnti-inflammatory panaceaThe expandingtherapeutics of interleukin-1 blockaderdquo Current Opinion inRheumatology vol 28 no 3 pp 197ndash203 2016
[91] C-H Chien M-J Lee H-C Liou H-H Liou and W-MFu ldquoLocal immunosuppressive microenvironment enhancesmigration of melanoma cells to lungs in DJ-1 knockout micerdquoPLoS ONE vol 10 no 2 Article ID e0115827 2015
[92] C Antonopoulos and G R Dubyak ldquoChemotherapy engagesmultiple pathways leading to IL-1120573 production by myeloidleukocytesrdquo OncoImmunology vol 3 no 1 Article ID e274992014
[93] E Ozaki M Campbell and S L Doyle ldquoTargeting the NLRP3inflammasome in chronic inflammatory diseases current per-spectivesrdquo Journal of Inflammation Research vol 8 pp 15ndash272015
[94] J H Hamman ldquoComposition and applications of Aloe vera leafgelrdquoMolecules vol 13 no 8 pp 1599ndash1616 2008
[95] L Langmead R J Makins and D S Rampton ldquoAnti-inflammatory effects of aloe vera gel in human colorectalmucosa in vitrordquo Alimentary Pharmacology and Therapeuticsvol 19 no 5 pp 521ndash527 2004
[96] N Yun C-H Lee and S-M Lee ldquoProtective effect of Aloe veraon polymicrobial sepsis inmicerdquo Food andChemical Toxicologyvol 47 no 6 pp 1341ndash1348 2009
[97] C S Yu F S Yu J K Chan et al ldquoAloe-emodin affects the levelsof cytokines and functions of leukocytes from Sprague-Dawleyratsrdquo In Vivo vol 20 no 4 pp 505ndash509 2006
[98] M Pulido-Moran J Moreno-Fernandez C Ramirez-Tortosaand M Ramirez-Tortosa ldquoCurcumin and healthrdquo Moleculesvol 21 no 3 article E264 2016
[99] Y-F Dong L-X Wang X Huang et al ldquoKir61 knock-down aggravates cerebral ischemiareperfusion-induced neuralinjury in micerdquo CNS Neuroscience and Therapeutics vol 19 no8 pp 617ndash624 2013
[100] P J Maier K Zemoura M A Acuna G E Yevenes HU Zeilhofer and D Benke ldquoIschemia-like oxygen and glu-cose deprivation mediates down-regulation of cell surface 120574-aminobutyric acidB receptors via the endoplasmic reticulum(ER) stress-induced transcription factor CCAATenhancer-binding protein (CEBP)-homologous protein (CHOP)rdquo TheJournal of Biological Chemistry vol 289 no 18 pp 12896ndash129072014
[101] H-Y Shin S-H Kim H-J Jeong et al ldquoEpigallocatechin-3-gallate inhibits secretion of TNF-120572 IL-6 and IL-8 through theattenuation of ERK and NF-120581B in HMC-1 cellsrdquo InternationalArchives of Allergy and Immunology vol 142 no 4 pp 335ndash3442007
[102] W P Pulskens L M Butter G J Teske et al ldquoNlrp3 preventsearly renal interstitial edema and vascular permeability inunilateral ureteral obstructionrdquo PLoS ONE vol 9 no 1 ArticleID e85775 2014
[103] S Kamath and C A Roobottom ldquoHyperdense pericardial effu-sion in dermatomyositis and contrast induced nephropathyrdquoEmergency Radiology vol 11 no 3 pp 177ndash179 2005
[104] T Akao K Kobashi and M Aburada ldquoEnzymic studies onthe animal and intestinal bacterial metabolism of geniposiderdquoBiological and Pharmaceutical Bulletin vol 17 no 12 pp 1573ndash1576 1994
[105] R Wang K C MoYung M H Zhang and K Poon ldquoUCP2-and non-UCP2-mediated electric current in eukaryotic cellsexhibits different propertiesrdquo Environmental Science and Pollu-tion Research vol 22 no 24 pp 19618ndash19631 2015
[106] J-M Lu Q Yao and C Chen ldquoGinseng compounds an updateon their molecular mechanisms and medical applicationsrdquoCurrent Vascular Pharmacology vol 7 no 3 pp 293ndash302 2009
[107] E Hernandez-Cuellar K Tsuchiya H Hara et al ldquoCuttingedge nitric oxide inhibits the NLRP3 inflammasomerdquo TheJournal of Immunology vol 189 no 11 pp 5113ndash5117 2012
[108] B B Mishra V A K Rathinam G W Martens et alldquoNitric oxide controls the immunopathology of tuberculosis byinhibiting NLRP3 inflammasome-dependent processing of IL-1120573rdquo Nature Immunology vol 14 no 1 pp 52ndash60 2013
[109] T Matsuno S-K Jung Y Matsumoto M Saito and JMorikawa ldquoPreferential cytotoxicity to tumor cells of 35-diprenyl-4-hydroxycinnamic acid (artepillin C) isolated frompropolisrdquo Anticancer Research vol 17 no 5A pp 3565ndash35681997
16 Mediators of Inflammation
[110] X Zhang J-H Zhang X-Y Chen et al ldquoReactive oxy-gen species-induced TXNIP drives fructose-mediated hepaticinflammation and lipid accumulation through NLRP3 inflam-masome activationrdquo Antioxidants and Redox Signaling vol 22no 10 pp 848ndash870 2015
[111] A Zendedel S Johann S Mehrabi et al ldquoActivation and reg-ulation of NLRP3 inflammasome by intrathecal application ofSDF-1a in a spinal cord injury modelrdquoMolecular Neurobiologyvol 53 no 5 pp 3063ndash3075 2016
[112] H Inoue and R Nakata ldquoResveratrol targets in inflammationrdquoEndocrineMetabolic and ImmuneDisordersmdashDrug Targets vol15 no 3 pp 186ndash195 2015
[113] S S Kulkarni and C Canto ldquoThe molecular targets of resver-atrolrdquo Biochimica et Biophysica Acta (BBA)mdashMolecular Basis ofDisease vol 1852 no 6 pp 1114ndash1123 2015
[114] C A Houghton R G Fassett and J S Coombes ldquoSul-foraphane translational research from laboratory bench toclinicrdquo Nutrition Reviews vol 71 no 11 pp 709ndash726 2013
[115] A T Dinkova-Kostova W D Holtzclaw R N Cole et alldquoDirect evidence that sulfhydryl groups of Keap1 are the sensorsregulating induction of phase 2 enzymes that protect againstcarcinogens and oxidantsrdquo Proceedings of the National Academyof Sciences of the United States of America vol 99 no 18 pp11908ndash11913 2002
[116] E Heiss C Herhaus K Klimo H Bartsch and C GerhauserldquoNuclear factor 120581B is a molecular target for sulforaphane-mediated anti-inflammatory mechanismsrdquo The Journal of Bio-logical Chemistry vol 276 no 34 pp 32008ndash32015 2001
[117] A Alfieri S Srivastava R C M Siow et al ldquoSulforaphanepreconditioning of the Nrf2HO-1 defense pathway protectsthe cerebral vasculature against blood-brain barrier disruptionand neurological deficits in strokerdquo Free Radical Biology andMedicine vol 65 pp 1012ndash1022 2013
[118] C Lee G H Park S-R Lee and J-H Jang ldquoAttenuation of120573 -amyloid-induced oxidative cell death by sulforaphane viaactivation of NF-E2-related factor 2rdquo Oxidative Medicine andCellular Longevity vol 2013 Article ID 313510 12 pages 2013
[119] E Barrajon-Catalan M Herranz-Lopez J Joven et al ldquoMolec-ular promiscuity of plant polyphenols in the management ofage-related diseases far beyond their antioxidant propertiesrdquoAdvances in Experimental Medicine and Biology vol 824 pp141ndash159 2014
[120] L Bravo ldquoPolyphenols chemistry dietary sources metabolismand nutritional significancerdquo Nutrition Reviews vol 56 no 11pp 317ndash333 1998
[121] D W Lamming J G Wood and D A Sinclair ldquoSmallmolecules that regulate lifespan evidence for xenohormesisrdquoMolecular Microbiology vol 53 no 4 pp 1003ndash1009 2004
[122] K T Howitz and D A Sinclair ldquoXenohormesis sensing thechemical cues of other speciesrdquo Cell vol 133 no 3 pp 387ndash3912008
[123] P L Hooper P L Hooper M Tytell and L Vıgh ldquoXeno-hormesis health benefits from an eon of plant stress responseevolutionrdquoCell Stress and Chaperones vol 15 no 6 pp 761ndash7702010
[124] B L Queen and T O Tollefsbol ldquoPolyphenols and agingrdquoCurrent Aging Science vol 3 no 1 pp 34ndash42 2010
[125] J A Baur and D A Sinclair ldquoTherapeutic potential of resvera-trol the in vivo evidencerdquo Nature Reviews Drug Discovery vol5 no 6 pp 493ndash506 2006
[126] R A Sharma A J Gescher and W P Steward ldquoCurcumin thestory so farrdquoEuropean Journal of Cancer vol 41 no 13 pp 1955ndash1968 2005
[127] K Milton ldquoMicronutrient intakes of wild primates are humansdifferentrdquo Comparative Biochemistry and Physiology Part AMolecular amp Integrative Physiology vol 136 no 1 pp 47ndash592003
moleculesrdquo ACS Chemical Biology vol 8 no 12 pp 2724ndash27332013
[49] K Nakahira J A Haspel V A K Rathinam et al ldquoAutophagyproteins regulate innate immune responses by inhibiting therelease of mitochondrial DNA mediated by the NALP3 inflam-masomerdquo Nature Immunology vol 12 no 3 pp 222ndash230 2011
[50] T Misawa M Takahama T Kozaki et al ldquoMicrotubule-drivenspatial arrangement ofmitochondria promotes activation of theNLRP3 inflammasomerdquo Nature Immunology vol 14 no 5 pp454ndash460 2013
[51] M M Budai A Varga S Milesz J Tozser and S BenkoldquoAloe vera downregulates LPS-induced inflammatory cytokineproduction and expression of NLRP3 inflammasome in humanmacrophagesrdquo Molecular Immunology vol 56 no 4 pp 471ndash479 2013
[52] J-W Han D-W Shim W-Y Shin et al ldquoAnti-inflammatoryeffect of emodin via attenuation of NLRP3 inflammasomeactivationrdquo International Journal of Molecular Sciences vol 16no 4 pp 8102ndash8109 2015
[53] Y Li J Li S Li et al ldquoCurcumin attenuates glutamate neurotox-icity in the hippocampus by suppression of ER stress-associatedTXNIPNLRP3 inflammasome activation in a manner depen-dent onAMPKrdquoToxicology andApplied Pharmacology vol 286no 1 pp 53ndash63 2015
[54] Z Gong J Zhou H Li et al ldquoCurcumin suppresses NLRP3inflammasome activation and protects against LPS-inducedseptic shockrdquo Molecular Nutrition and Food Research vol 59no 11 pp 2132ndash2142 2015
[55] P-Y Tsai S-M Ka J-M Chang et al ldquoEpigallocatechin-3-gallate prevents lupus nephritis development in mice viaenhancing the Nrf2 antioxidant pathway and inhibiting NLRP3inflammasome activationrdquo Free Radical Biology and Medicinevol 51 no 3 pp 744ndash754 2011
[56] Z Gao Y Han Y Hu et al ldquoTargeting HO-1 byepigallocatechin-3-gallate reduces contrast-induced renalinjury via anti-oxidative stress and anti-inflammationpathwaysrdquo PLOS ONE vol 11 no 2 article e0149032 2016
[57] V Rajanbabu L Galam J Fukumoto et al ldquoGenipin suppressesNLRP3 inflammasome activation through uncoupling protein-2rdquo Cellular Immunology vol 297 no 1 pp 40ndash45 2015
[58] S-X Yu C-T DuW Chen et al ldquoGenipin inhibits NLRP3 andNLRC4 inflammasome activation via autophagy suppressionrdquoScientific Reports vol 5 article 17935 2015
[59] J Kim H Ahn B-C Han et al ldquoKorean red ginseng extractsinhibit NLRP3 and AIM2 inflammasome activationrdquo Immunol-ogy Letters vol 158 no 1-2 pp 143ndash150 2014
[60] S-J Yoon J-Y Park S Choi et al ldquoGinsenoside Rg3 regulatesS-nitrosylation of the NLRP3 inflammasome via suppression ofiNOSrdquo Biochemical and Biophysical Research Communicationsvol 463 no 4 pp 1184ndash1189 2015
[61] J Song J Li F Hou X Wang and B Liu ldquoMangiferininhibits endoplasmic reticulum stress-associated thioredoxin-interacting proteinNLRP3 inflammasome activation with reg-ulation of AMPK in endothelial cellsrdquo Metabolism vol 64 no3 pp 428ndash437 2015
[62] C-W Pan Z-Z Pan J-J Hu et al ldquoMangiferin alleviateslipopolysaccharide and D-galactosamine-induced acute liverinjury by activating the Nrf2 pathway and inhibiting NLRP3inflammasome activationrdquo European Journal of Pharmacologyvol 770 pp 85ndash91 2016
[63] J I Hori D S Zamboni D B Carrao GHGoldman andAABerretta ldquoThe inhibition of inflammasome by Brazilian propo-lis (EPP-AF)rdquo Evidence-Based Complementary and AlternativeMedicine vol 2013 Article ID 418508 11 pages 2013
[64] C Wang Y Pan Q-Y Zhang F-M Wang and L-D KongldquoQuercetin and allopurinol ameliorate kidney injury in STZ-treated rats with regulation of renal NLRP3 inflammasomeactivation and lipid accumulationrdquo PLoS ONE vol 7 no 6Article ID e38285 2012
[65] Q-H Hu X Zhang Y Pan Y-C Li and L-D Kong ldquoAllop-urinol quercetin and rutin ameliorate renal NLRP3 inflamma-some activation and lipid accumulation in fructose-fed ratsrdquoBiochemical Pharmacology vol 84 no 1 pp 113ndash125 2012
[66] WWangCWangX-QDing et al ldquoQuercetin and allopurinolreduce liver thioredoxin-interacting protein to alleviate inflam-mation and lipid accumulation in diabetic ratsrdquo British Journalof Pharmacology vol 169 no 6 pp 1352ndash1371 2013
[67] Q-Y Zhang Y Pan R Wang et al ldquoQuercetin inhibitsAMPKTXNIP activation and reduces inflammatory lesions toimprove insulin signaling defect in the hypothalamus of highfructose-fed ratsrdquo Journal of Nutritional Biochemistry vol 25no 4 pp 420ndash428 2014
[68] J Wu X Xu Y Li et al ldquoQuercetin luteolin and epigallo-catechin gallate alleviate TXNIP and NLRP3-mediated inflam-mation and apoptosis with regulation of AMPK in endothelialcellsrdquo European Journal of Pharmacology vol 745 pp 59ndash682015
[69] W Jiang Y Huang N Han et al ldquoQuercetin suppresses NLRP3inflammasome activation and attenuates histopathology in a ratmodel of spinal cord injuryrdquo Spinal Cord vol 54 pp 592ndash5962016
[70] Y Fu Y Wang L Du et al ldquoResveratrol inhibits ionisingirradiation-induced inflammation in MSCs by activating Sirt1and limiting NLRP-3 inflammasome activationrdquo InternationalJournal ofMolecular Sciences vol 14 no 7 pp 14105ndash14118 2013
[71] T-T Huang H-C Lai Y-B Chen et al ldquoCis-Resveratrolproduces anti-inflammatory effects by inhibiting canonicaland non-canonical inflammasomes in macrophagesrdquo InnateImmunity vol 20 no 7 pp 735ndash750 2014
[72] Y-P Chang S-M Ka W-H Hsu et al ldquoResveratrol inhibitsNLRP3 inflammasome activation by preserving mitochondrialintegrity and augmenting autophagyrdquo Journal of Cellular Physi-ology vol 230 no 7 pp 1567ndash1579 2015
[73] S J Yang and Y Lim ldquoResveratrol ameliorates hepaticmetaflammation and inhibits NLRP3 inflammasome activa-tionrdquoMetabolism vol 63 no 5 pp 693ndash701 2014
[74] D-M Sui Q Xie W-J Yi et al ldquoResveratrol protects againstsepsis-associated encephalopathy and inhibits the NLRP3IL-1 120573 axis in microgliardquo Mediators of Inflammation vol 2016Article ID 1045657 10 pages 2016
[75] J Wu X Li G Zhu Y Zhang M He and J Zhang ldquoTherole of Resveratrol-inducedmitophagyautophagy in peritonealmesothelial cells inflammatory injury via NLRP3 inflamma-some activation triggered bymitochondrial ROSrdquoExperimentalCell Research vol 341 no 1 pp 42ndash53 2016
[76] Y W An K A Jhang S Y Woo J L Kang and Y HChong ldquoSulforaphane exerts its anti-inflammatory effectagainst amyloid-120573 peptide via STAT-1 dephosphorylationand activation of Nrf2HO-1 cascade in human THP-1macrophagesrdquo Neurobiology of Aging vol 38 pp 1ndash10 2016
[77] G Yang H E Lee and J Y Lee ldquoA pharmacological inhibitorof NLRP3 inflammasome prevents non-alcoholic fatty liver
Mediators of Inflammation 15
disease in a mouse model induced by high fat dietrdquo ScientificReports vol 6 Article ID 24399 2016
[78] L Franchi R Munoz-Planillo and G Nunez ldquoSensing andreacting to microbes through the inflammasomesrdquo NatureImmunology vol 13 no 4 pp 325ndash332 2012
[79] S L Cassel and F S Sutterwala ldquoSterile inflammatory responsesmediated by the NLRP3 inflammasomerdquo European Journal ofImmunology vol 40 no 3 pp 607ndash611 2010
[80] M-S Tan J-T Yu T Jiang X-C Zhu and L Tan ldquoThe NLRP3inflammasome in alzheimerrsquos diseaserdquoMolecular Neurobiologyvol 48 no 3 pp 875ndash882 2013
[81] M Gold and J El Khoury ldquo120573-amyloid microglia andthe inflammasome in Alzheimerrsquos diseaserdquo Seminars inImmunopathology vol 37 no 6 pp 607ndash611 2015
[82] P M Peeters T N Perkins E F M Wouters B T Mossmanand N L Reynaert ldquoSilica induces NLRP3 inflammasomeactivation in human lung epithelial cellsrdquo Particle and FibreToxicology vol 10 no 1 article 3 2013
[83] H Watanabe O Gaide V Petrilli et al ldquoActivation of the IL-1120573-processing inflammasome is involved in contact hypersen-sitivityrdquo Journal of Investigative Dermatology vol 127 no 8 pp1956ndash1963 2007
[84] X Dai K Sayama M Tohyama et al ldquoMite allergen is adanger signal for the skin via activation of inflammasome inkeratinocytesrdquo Journal of Allergy and Clinical Immunology vol127 no 3 pp 806ndash814 2011
[85] A Varga M M Budai S Milesz A Bacsi J Tozser and SBenko ldquoRagweed pollen extract intensifies lipopolysaccharide-induced priming of NLRP3 inflammasome in humanmacrophagesrdquo Immunology vol 138 no 4 pp 392ndash4012013
[86] B Vandanmagsar Y-H Youm A Ravussin et al ldquoThe NLRP3inflammasome instigates obesity-induced inflammation andinsulin resistancerdquo Nature Medicine vol 17 no 2 pp 179ndash1892011
[87] H Wen D Gris Y Lei et al ldquoFatty acid-induced NLRP3-ASCinflammasome activation interferes with insulin signalingrdquoNature Immunology vol 12 no 5 pp 408ndash415 2011
[88] L Liang X Tan Q Zhou et al ldquoIL-1120573 triggered by pepti-doglycan and lipopolysaccharide through TLR24 and ROS-NLRP3 inflammasome- dependent pathways is involved inocular behcetrsquos diseaserdquo Investigative Ophthalmology and VisualScience vol 54 no 1 pp 402ndash414 2013
[89] S Rosengren H M Hoffman W Bugbee and D L BoyleldquoExpression and regulation of cryopyrin and related proteinsin rheumatoid arthritis synoviumrdquo Annals of the RheumaticDiseases vol 64 no 5 pp 708ndash714 2005
[90] J M Kahlenberg ldquoAnti-inflammatory panaceaThe expandingtherapeutics of interleukin-1 blockaderdquo Current Opinion inRheumatology vol 28 no 3 pp 197ndash203 2016
[91] C-H Chien M-J Lee H-C Liou H-H Liou and W-MFu ldquoLocal immunosuppressive microenvironment enhancesmigration of melanoma cells to lungs in DJ-1 knockout micerdquoPLoS ONE vol 10 no 2 Article ID e0115827 2015
[92] C Antonopoulos and G R Dubyak ldquoChemotherapy engagesmultiple pathways leading to IL-1120573 production by myeloidleukocytesrdquo OncoImmunology vol 3 no 1 Article ID e274992014
[93] E Ozaki M Campbell and S L Doyle ldquoTargeting the NLRP3inflammasome in chronic inflammatory diseases current per-spectivesrdquo Journal of Inflammation Research vol 8 pp 15ndash272015
[94] J H Hamman ldquoComposition and applications of Aloe vera leafgelrdquoMolecules vol 13 no 8 pp 1599ndash1616 2008
[95] L Langmead R J Makins and D S Rampton ldquoAnti-inflammatory effects of aloe vera gel in human colorectalmucosa in vitrordquo Alimentary Pharmacology and Therapeuticsvol 19 no 5 pp 521ndash527 2004
[96] N Yun C-H Lee and S-M Lee ldquoProtective effect of Aloe veraon polymicrobial sepsis inmicerdquo Food andChemical Toxicologyvol 47 no 6 pp 1341ndash1348 2009
[97] C S Yu F S Yu J K Chan et al ldquoAloe-emodin affects the levelsof cytokines and functions of leukocytes from Sprague-Dawleyratsrdquo In Vivo vol 20 no 4 pp 505ndash509 2006
[98] M Pulido-Moran J Moreno-Fernandez C Ramirez-Tortosaand M Ramirez-Tortosa ldquoCurcumin and healthrdquo Moleculesvol 21 no 3 article E264 2016
[99] Y-F Dong L-X Wang X Huang et al ldquoKir61 knock-down aggravates cerebral ischemiareperfusion-induced neuralinjury in micerdquo CNS Neuroscience and Therapeutics vol 19 no8 pp 617ndash624 2013
[100] P J Maier K Zemoura M A Acuna G E Yevenes HU Zeilhofer and D Benke ldquoIschemia-like oxygen and glu-cose deprivation mediates down-regulation of cell surface 120574-aminobutyric acidB receptors via the endoplasmic reticulum(ER) stress-induced transcription factor CCAATenhancer-binding protein (CEBP)-homologous protein (CHOP)rdquo TheJournal of Biological Chemistry vol 289 no 18 pp 12896ndash129072014
[101] H-Y Shin S-H Kim H-J Jeong et al ldquoEpigallocatechin-3-gallate inhibits secretion of TNF-120572 IL-6 and IL-8 through theattenuation of ERK and NF-120581B in HMC-1 cellsrdquo InternationalArchives of Allergy and Immunology vol 142 no 4 pp 335ndash3442007
[102] W P Pulskens L M Butter G J Teske et al ldquoNlrp3 preventsearly renal interstitial edema and vascular permeability inunilateral ureteral obstructionrdquo PLoS ONE vol 9 no 1 ArticleID e85775 2014
[103] S Kamath and C A Roobottom ldquoHyperdense pericardial effu-sion in dermatomyositis and contrast induced nephropathyrdquoEmergency Radiology vol 11 no 3 pp 177ndash179 2005
[104] T Akao K Kobashi and M Aburada ldquoEnzymic studies onthe animal and intestinal bacterial metabolism of geniposiderdquoBiological and Pharmaceutical Bulletin vol 17 no 12 pp 1573ndash1576 1994
[105] R Wang K C MoYung M H Zhang and K Poon ldquoUCP2-and non-UCP2-mediated electric current in eukaryotic cellsexhibits different propertiesrdquo Environmental Science and Pollu-tion Research vol 22 no 24 pp 19618ndash19631 2015
[106] J-M Lu Q Yao and C Chen ldquoGinseng compounds an updateon their molecular mechanisms and medical applicationsrdquoCurrent Vascular Pharmacology vol 7 no 3 pp 293ndash302 2009
[107] E Hernandez-Cuellar K Tsuchiya H Hara et al ldquoCuttingedge nitric oxide inhibits the NLRP3 inflammasomerdquo TheJournal of Immunology vol 189 no 11 pp 5113ndash5117 2012
[108] B B Mishra V A K Rathinam G W Martens et alldquoNitric oxide controls the immunopathology of tuberculosis byinhibiting NLRP3 inflammasome-dependent processing of IL-1120573rdquo Nature Immunology vol 14 no 1 pp 52ndash60 2013
[109] T Matsuno S-K Jung Y Matsumoto M Saito and JMorikawa ldquoPreferential cytotoxicity to tumor cells of 35-diprenyl-4-hydroxycinnamic acid (artepillin C) isolated frompropolisrdquo Anticancer Research vol 17 no 5A pp 3565ndash35681997
16 Mediators of Inflammation
[110] X Zhang J-H Zhang X-Y Chen et al ldquoReactive oxy-gen species-induced TXNIP drives fructose-mediated hepaticinflammation and lipid accumulation through NLRP3 inflam-masome activationrdquo Antioxidants and Redox Signaling vol 22no 10 pp 848ndash870 2015
[111] A Zendedel S Johann S Mehrabi et al ldquoActivation and reg-ulation of NLRP3 inflammasome by intrathecal application ofSDF-1a in a spinal cord injury modelrdquoMolecular Neurobiologyvol 53 no 5 pp 3063ndash3075 2016
[112] H Inoue and R Nakata ldquoResveratrol targets in inflammationrdquoEndocrineMetabolic and ImmuneDisordersmdashDrug Targets vol15 no 3 pp 186ndash195 2015
[113] S S Kulkarni and C Canto ldquoThe molecular targets of resver-atrolrdquo Biochimica et Biophysica Acta (BBA)mdashMolecular Basis ofDisease vol 1852 no 6 pp 1114ndash1123 2015
[114] C A Houghton R G Fassett and J S Coombes ldquoSul-foraphane translational research from laboratory bench toclinicrdquo Nutrition Reviews vol 71 no 11 pp 709ndash726 2013
[115] A T Dinkova-Kostova W D Holtzclaw R N Cole et alldquoDirect evidence that sulfhydryl groups of Keap1 are the sensorsregulating induction of phase 2 enzymes that protect againstcarcinogens and oxidantsrdquo Proceedings of the National Academyof Sciences of the United States of America vol 99 no 18 pp11908ndash11913 2002
[116] E Heiss C Herhaus K Klimo H Bartsch and C GerhauserldquoNuclear factor 120581B is a molecular target for sulforaphane-mediated anti-inflammatory mechanismsrdquo The Journal of Bio-logical Chemistry vol 276 no 34 pp 32008ndash32015 2001
[117] A Alfieri S Srivastava R C M Siow et al ldquoSulforaphanepreconditioning of the Nrf2HO-1 defense pathway protectsthe cerebral vasculature against blood-brain barrier disruptionand neurological deficits in strokerdquo Free Radical Biology andMedicine vol 65 pp 1012ndash1022 2013
[118] C Lee G H Park S-R Lee and J-H Jang ldquoAttenuation of120573 -amyloid-induced oxidative cell death by sulforaphane viaactivation of NF-E2-related factor 2rdquo Oxidative Medicine andCellular Longevity vol 2013 Article ID 313510 12 pages 2013
[119] E Barrajon-Catalan M Herranz-Lopez J Joven et al ldquoMolec-ular promiscuity of plant polyphenols in the management ofage-related diseases far beyond their antioxidant propertiesrdquoAdvances in Experimental Medicine and Biology vol 824 pp141ndash159 2014
[120] L Bravo ldquoPolyphenols chemistry dietary sources metabolismand nutritional significancerdquo Nutrition Reviews vol 56 no 11pp 317ndash333 1998
[121] D W Lamming J G Wood and D A Sinclair ldquoSmallmolecules that regulate lifespan evidence for xenohormesisrdquoMolecular Microbiology vol 53 no 4 pp 1003ndash1009 2004
[122] K T Howitz and D A Sinclair ldquoXenohormesis sensing thechemical cues of other speciesrdquo Cell vol 133 no 3 pp 387ndash3912008
[123] P L Hooper P L Hooper M Tytell and L Vıgh ldquoXeno-hormesis health benefits from an eon of plant stress responseevolutionrdquoCell Stress and Chaperones vol 15 no 6 pp 761ndash7702010
[124] B L Queen and T O Tollefsbol ldquoPolyphenols and agingrdquoCurrent Aging Science vol 3 no 1 pp 34ndash42 2010
[125] J A Baur and D A Sinclair ldquoTherapeutic potential of resvera-trol the in vivo evidencerdquo Nature Reviews Drug Discovery vol5 no 6 pp 493ndash506 2006
[126] R A Sharma A J Gescher and W P Steward ldquoCurcumin thestory so farrdquoEuropean Journal of Cancer vol 41 no 13 pp 1955ndash1968 2005
[127] K Milton ldquoMicronutrient intakes of wild primates are humansdifferentrdquo Comparative Biochemistry and Physiology Part AMolecular amp Integrative Physiology vol 136 no 1 pp 47ndash592003
disease in a mouse model induced by high fat dietrdquo ScientificReports vol 6 Article ID 24399 2016
[78] L Franchi R Munoz-Planillo and G Nunez ldquoSensing andreacting to microbes through the inflammasomesrdquo NatureImmunology vol 13 no 4 pp 325ndash332 2012
[79] S L Cassel and F S Sutterwala ldquoSterile inflammatory responsesmediated by the NLRP3 inflammasomerdquo European Journal ofImmunology vol 40 no 3 pp 607ndash611 2010
[80] M-S Tan J-T Yu T Jiang X-C Zhu and L Tan ldquoThe NLRP3inflammasome in alzheimerrsquos diseaserdquoMolecular Neurobiologyvol 48 no 3 pp 875ndash882 2013
[81] M Gold and J El Khoury ldquo120573-amyloid microglia andthe inflammasome in Alzheimerrsquos diseaserdquo Seminars inImmunopathology vol 37 no 6 pp 607ndash611 2015
[82] P M Peeters T N Perkins E F M Wouters B T Mossmanand N L Reynaert ldquoSilica induces NLRP3 inflammasomeactivation in human lung epithelial cellsrdquo Particle and FibreToxicology vol 10 no 1 article 3 2013
[83] H Watanabe O Gaide V Petrilli et al ldquoActivation of the IL-1120573-processing inflammasome is involved in contact hypersen-sitivityrdquo Journal of Investigative Dermatology vol 127 no 8 pp1956ndash1963 2007
[84] X Dai K Sayama M Tohyama et al ldquoMite allergen is adanger signal for the skin via activation of inflammasome inkeratinocytesrdquo Journal of Allergy and Clinical Immunology vol127 no 3 pp 806ndash814 2011
[85] A Varga M M Budai S Milesz A Bacsi J Tozser and SBenko ldquoRagweed pollen extract intensifies lipopolysaccharide-induced priming of NLRP3 inflammasome in humanmacrophagesrdquo Immunology vol 138 no 4 pp 392ndash4012013
[86] B Vandanmagsar Y-H Youm A Ravussin et al ldquoThe NLRP3inflammasome instigates obesity-induced inflammation andinsulin resistancerdquo Nature Medicine vol 17 no 2 pp 179ndash1892011
[87] H Wen D Gris Y Lei et al ldquoFatty acid-induced NLRP3-ASCinflammasome activation interferes with insulin signalingrdquoNature Immunology vol 12 no 5 pp 408ndash415 2011
[88] L Liang X Tan Q Zhou et al ldquoIL-1120573 triggered by pepti-doglycan and lipopolysaccharide through TLR24 and ROS-NLRP3 inflammasome- dependent pathways is involved inocular behcetrsquos diseaserdquo Investigative Ophthalmology and VisualScience vol 54 no 1 pp 402ndash414 2013
[89] S Rosengren H M Hoffman W Bugbee and D L BoyleldquoExpression and regulation of cryopyrin and related proteinsin rheumatoid arthritis synoviumrdquo Annals of the RheumaticDiseases vol 64 no 5 pp 708ndash714 2005
[90] J M Kahlenberg ldquoAnti-inflammatory panaceaThe expandingtherapeutics of interleukin-1 blockaderdquo Current Opinion inRheumatology vol 28 no 3 pp 197ndash203 2016
[91] C-H Chien M-J Lee H-C Liou H-H Liou and W-MFu ldquoLocal immunosuppressive microenvironment enhancesmigration of melanoma cells to lungs in DJ-1 knockout micerdquoPLoS ONE vol 10 no 2 Article ID e0115827 2015
[92] C Antonopoulos and G R Dubyak ldquoChemotherapy engagesmultiple pathways leading to IL-1120573 production by myeloidleukocytesrdquo OncoImmunology vol 3 no 1 Article ID e274992014
[93] E Ozaki M Campbell and S L Doyle ldquoTargeting the NLRP3inflammasome in chronic inflammatory diseases current per-spectivesrdquo Journal of Inflammation Research vol 8 pp 15ndash272015
[94] J H Hamman ldquoComposition and applications of Aloe vera leafgelrdquoMolecules vol 13 no 8 pp 1599ndash1616 2008
[95] L Langmead R J Makins and D S Rampton ldquoAnti-inflammatory effects of aloe vera gel in human colorectalmucosa in vitrordquo Alimentary Pharmacology and Therapeuticsvol 19 no 5 pp 521ndash527 2004
[96] N Yun C-H Lee and S-M Lee ldquoProtective effect of Aloe veraon polymicrobial sepsis inmicerdquo Food andChemical Toxicologyvol 47 no 6 pp 1341ndash1348 2009
[97] C S Yu F S Yu J K Chan et al ldquoAloe-emodin affects the levelsof cytokines and functions of leukocytes from Sprague-Dawleyratsrdquo In Vivo vol 20 no 4 pp 505ndash509 2006
[98] M Pulido-Moran J Moreno-Fernandez C Ramirez-Tortosaand M Ramirez-Tortosa ldquoCurcumin and healthrdquo Moleculesvol 21 no 3 article E264 2016
[99] Y-F Dong L-X Wang X Huang et al ldquoKir61 knock-down aggravates cerebral ischemiareperfusion-induced neuralinjury in micerdquo CNS Neuroscience and Therapeutics vol 19 no8 pp 617ndash624 2013
[100] P J Maier K Zemoura M A Acuna G E Yevenes HU Zeilhofer and D Benke ldquoIschemia-like oxygen and glu-cose deprivation mediates down-regulation of cell surface 120574-aminobutyric acidB receptors via the endoplasmic reticulum(ER) stress-induced transcription factor CCAATenhancer-binding protein (CEBP)-homologous protein (CHOP)rdquo TheJournal of Biological Chemistry vol 289 no 18 pp 12896ndash129072014
[101] H-Y Shin S-H Kim H-J Jeong et al ldquoEpigallocatechin-3-gallate inhibits secretion of TNF-120572 IL-6 and IL-8 through theattenuation of ERK and NF-120581B in HMC-1 cellsrdquo InternationalArchives of Allergy and Immunology vol 142 no 4 pp 335ndash3442007
[102] W P Pulskens L M Butter G J Teske et al ldquoNlrp3 preventsearly renal interstitial edema and vascular permeability inunilateral ureteral obstructionrdquo PLoS ONE vol 9 no 1 ArticleID e85775 2014
[103] S Kamath and C A Roobottom ldquoHyperdense pericardial effu-sion in dermatomyositis and contrast induced nephropathyrdquoEmergency Radiology vol 11 no 3 pp 177ndash179 2005
[104] T Akao K Kobashi and M Aburada ldquoEnzymic studies onthe animal and intestinal bacterial metabolism of geniposiderdquoBiological and Pharmaceutical Bulletin vol 17 no 12 pp 1573ndash1576 1994
[105] R Wang K C MoYung M H Zhang and K Poon ldquoUCP2-and non-UCP2-mediated electric current in eukaryotic cellsexhibits different propertiesrdquo Environmental Science and Pollu-tion Research vol 22 no 24 pp 19618ndash19631 2015
[106] J-M Lu Q Yao and C Chen ldquoGinseng compounds an updateon their molecular mechanisms and medical applicationsrdquoCurrent Vascular Pharmacology vol 7 no 3 pp 293ndash302 2009
[107] E Hernandez-Cuellar K Tsuchiya H Hara et al ldquoCuttingedge nitric oxide inhibits the NLRP3 inflammasomerdquo TheJournal of Immunology vol 189 no 11 pp 5113ndash5117 2012
[108] B B Mishra V A K Rathinam G W Martens et alldquoNitric oxide controls the immunopathology of tuberculosis byinhibiting NLRP3 inflammasome-dependent processing of IL-1120573rdquo Nature Immunology vol 14 no 1 pp 52ndash60 2013
[109] T Matsuno S-K Jung Y Matsumoto M Saito and JMorikawa ldquoPreferential cytotoxicity to tumor cells of 35-diprenyl-4-hydroxycinnamic acid (artepillin C) isolated frompropolisrdquo Anticancer Research vol 17 no 5A pp 3565ndash35681997
16 Mediators of Inflammation
[110] X Zhang J-H Zhang X-Y Chen et al ldquoReactive oxy-gen species-induced TXNIP drives fructose-mediated hepaticinflammation and lipid accumulation through NLRP3 inflam-masome activationrdquo Antioxidants and Redox Signaling vol 22no 10 pp 848ndash870 2015
[111] A Zendedel S Johann S Mehrabi et al ldquoActivation and reg-ulation of NLRP3 inflammasome by intrathecal application ofSDF-1a in a spinal cord injury modelrdquoMolecular Neurobiologyvol 53 no 5 pp 3063ndash3075 2016
[112] H Inoue and R Nakata ldquoResveratrol targets in inflammationrdquoEndocrineMetabolic and ImmuneDisordersmdashDrug Targets vol15 no 3 pp 186ndash195 2015
[113] S S Kulkarni and C Canto ldquoThe molecular targets of resver-atrolrdquo Biochimica et Biophysica Acta (BBA)mdashMolecular Basis ofDisease vol 1852 no 6 pp 1114ndash1123 2015
[114] C A Houghton R G Fassett and J S Coombes ldquoSul-foraphane translational research from laboratory bench toclinicrdquo Nutrition Reviews vol 71 no 11 pp 709ndash726 2013
[115] A T Dinkova-Kostova W D Holtzclaw R N Cole et alldquoDirect evidence that sulfhydryl groups of Keap1 are the sensorsregulating induction of phase 2 enzymes that protect againstcarcinogens and oxidantsrdquo Proceedings of the National Academyof Sciences of the United States of America vol 99 no 18 pp11908ndash11913 2002
[116] E Heiss C Herhaus K Klimo H Bartsch and C GerhauserldquoNuclear factor 120581B is a molecular target for sulforaphane-mediated anti-inflammatory mechanismsrdquo The Journal of Bio-logical Chemistry vol 276 no 34 pp 32008ndash32015 2001
[117] A Alfieri S Srivastava R C M Siow et al ldquoSulforaphanepreconditioning of the Nrf2HO-1 defense pathway protectsthe cerebral vasculature against blood-brain barrier disruptionand neurological deficits in strokerdquo Free Radical Biology andMedicine vol 65 pp 1012ndash1022 2013
[118] C Lee G H Park S-R Lee and J-H Jang ldquoAttenuation of120573 -amyloid-induced oxidative cell death by sulforaphane viaactivation of NF-E2-related factor 2rdquo Oxidative Medicine andCellular Longevity vol 2013 Article ID 313510 12 pages 2013
[119] E Barrajon-Catalan M Herranz-Lopez J Joven et al ldquoMolec-ular promiscuity of plant polyphenols in the management ofage-related diseases far beyond their antioxidant propertiesrdquoAdvances in Experimental Medicine and Biology vol 824 pp141ndash159 2014
[120] L Bravo ldquoPolyphenols chemistry dietary sources metabolismand nutritional significancerdquo Nutrition Reviews vol 56 no 11pp 317ndash333 1998
[121] D W Lamming J G Wood and D A Sinclair ldquoSmallmolecules that regulate lifespan evidence for xenohormesisrdquoMolecular Microbiology vol 53 no 4 pp 1003ndash1009 2004
[122] K T Howitz and D A Sinclair ldquoXenohormesis sensing thechemical cues of other speciesrdquo Cell vol 133 no 3 pp 387ndash3912008
[123] P L Hooper P L Hooper M Tytell and L Vıgh ldquoXeno-hormesis health benefits from an eon of plant stress responseevolutionrdquoCell Stress and Chaperones vol 15 no 6 pp 761ndash7702010
[124] B L Queen and T O Tollefsbol ldquoPolyphenols and agingrdquoCurrent Aging Science vol 3 no 1 pp 34ndash42 2010
[125] J A Baur and D A Sinclair ldquoTherapeutic potential of resvera-trol the in vivo evidencerdquo Nature Reviews Drug Discovery vol5 no 6 pp 493ndash506 2006
[126] R A Sharma A J Gescher and W P Steward ldquoCurcumin thestory so farrdquoEuropean Journal of Cancer vol 41 no 13 pp 1955ndash1968 2005
[127] K Milton ldquoMicronutrient intakes of wild primates are humansdifferentrdquo Comparative Biochemistry and Physiology Part AMolecular amp Integrative Physiology vol 136 no 1 pp 47ndash592003
[110] X Zhang J-H Zhang X-Y Chen et al ldquoReactive oxy-gen species-induced TXNIP drives fructose-mediated hepaticinflammation and lipid accumulation through NLRP3 inflam-masome activationrdquo Antioxidants and Redox Signaling vol 22no 10 pp 848ndash870 2015
[111] A Zendedel S Johann S Mehrabi et al ldquoActivation and reg-ulation of NLRP3 inflammasome by intrathecal application ofSDF-1a in a spinal cord injury modelrdquoMolecular Neurobiologyvol 53 no 5 pp 3063ndash3075 2016
[112] H Inoue and R Nakata ldquoResveratrol targets in inflammationrdquoEndocrineMetabolic and ImmuneDisordersmdashDrug Targets vol15 no 3 pp 186ndash195 2015
[113] S S Kulkarni and C Canto ldquoThe molecular targets of resver-atrolrdquo Biochimica et Biophysica Acta (BBA)mdashMolecular Basis ofDisease vol 1852 no 6 pp 1114ndash1123 2015
[114] C A Houghton R G Fassett and J S Coombes ldquoSul-foraphane translational research from laboratory bench toclinicrdquo Nutrition Reviews vol 71 no 11 pp 709ndash726 2013
[115] A T Dinkova-Kostova W D Holtzclaw R N Cole et alldquoDirect evidence that sulfhydryl groups of Keap1 are the sensorsregulating induction of phase 2 enzymes that protect againstcarcinogens and oxidantsrdquo Proceedings of the National Academyof Sciences of the United States of America vol 99 no 18 pp11908ndash11913 2002
[116] E Heiss C Herhaus K Klimo H Bartsch and C GerhauserldquoNuclear factor 120581B is a molecular target for sulforaphane-mediated anti-inflammatory mechanismsrdquo The Journal of Bio-logical Chemistry vol 276 no 34 pp 32008ndash32015 2001
[117] A Alfieri S Srivastava R C M Siow et al ldquoSulforaphanepreconditioning of the Nrf2HO-1 defense pathway protectsthe cerebral vasculature against blood-brain barrier disruptionand neurological deficits in strokerdquo Free Radical Biology andMedicine vol 65 pp 1012ndash1022 2013
[118] C Lee G H Park S-R Lee and J-H Jang ldquoAttenuation of120573 -amyloid-induced oxidative cell death by sulforaphane viaactivation of NF-E2-related factor 2rdquo Oxidative Medicine andCellular Longevity vol 2013 Article ID 313510 12 pages 2013
[119] E Barrajon-Catalan M Herranz-Lopez J Joven et al ldquoMolec-ular promiscuity of plant polyphenols in the management ofage-related diseases far beyond their antioxidant propertiesrdquoAdvances in Experimental Medicine and Biology vol 824 pp141ndash159 2014
[120] L Bravo ldquoPolyphenols chemistry dietary sources metabolismand nutritional significancerdquo Nutrition Reviews vol 56 no 11pp 317ndash333 1998
[121] D W Lamming J G Wood and D A Sinclair ldquoSmallmolecules that regulate lifespan evidence for xenohormesisrdquoMolecular Microbiology vol 53 no 4 pp 1003ndash1009 2004
[122] K T Howitz and D A Sinclair ldquoXenohormesis sensing thechemical cues of other speciesrdquo Cell vol 133 no 3 pp 387ndash3912008
[123] P L Hooper P L Hooper M Tytell and L Vıgh ldquoXeno-hormesis health benefits from an eon of plant stress responseevolutionrdquoCell Stress and Chaperones vol 15 no 6 pp 761ndash7702010
[124] B L Queen and T O Tollefsbol ldquoPolyphenols and agingrdquoCurrent Aging Science vol 3 no 1 pp 34ndash42 2010
[125] J A Baur and D A Sinclair ldquoTherapeutic potential of resvera-trol the in vivo evidencerdquo Nature Reviews Drug Discovery vol5 no 6 pp 493ndash506 2006
[126] R A Sharma A J Gescher and W P Steward ldquoCurcumin thestory so farrdquoEuropean Journal of Cancer vol 41 no 13 pp 1955ndash1968 2005
[127] K Milton ldquoMicronutrient intakes of wild primates are humansdifferentrdquo Comparative Biochemistry and Physiology Part AMolecular amp Integrative Physiology vol 136 no 1 pp 47ndash592003
