REVIEW Toll like receptor (TLR)-induced differential expression of microRNAs (MiRs) and immune response against infection: A systematic review Seyed Hossein Aalaei-andabili a , Nima Rezaei a,b,c,d, * a Molecular Immunology Research Center, Tehran University of Medical Sciences, Tehran, Iran b Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran c Research Center for Immunodeficiencies, Pediatrics Center of Excellence, Children’s Medical Center, Tehran University of Medical Sciences, Tehran, Iran d Department of Infection and Immunity, School of Medicine and Biomedical Sciences, The University of Sheffield, Sheffield, UK Accepted 6 July 2013 Available online 12 July 2013 KEYWORDS MicroRNAs; Toll-like receptors; Infection Summary Toll like receptors (TLRs) are one of the major families of pattern recognition re- ceptors (PRRs). MicroRNAs (MiRs) are small noncoding RNAs with regulatory effects on biolog- ical process, and it has been recently shown that they can control inflammatory process and the response to an infection by modulating the function of TLRs. In this study, we designed a systematic review to clarify the reciprocal interaction between TLRs and MiRs, in order to identify possible future therapeutic targets and strategies. On the one hand, TLRs stimulation can change expression level of miRs in various ways, which can lead to modulating their ef- fects. On the other hand, MiRs also influence the expression of TLRs and the intensity of the inflammatory reaction. We therefore conclude that the interaction between MiRs and TLRs is a key regulator of innate immune system. Investigations discovering therapeutic approaches Abbreviations: LPS, lipopolysaccharides; p38MAPK, mitogen-activated protein kinas p38; MKP-1, MAPK phosphatase-1; SMRT, silencing mediator for retinoid and thyroid hormone receptor; Pnak1-a, pantothenate kinas 1-a; C/EBPb, CCAAT/enhancer-binding protein b; SOCS4, Suppressor of cytokine signaling; CIS, cytokine-inducible SH2 protein; HIF1-a, hypoxia inducible factor; CaMKII, Calcium/calmodul independent protein kinase II; MHC II, major histocompatibility complex class II; TAB2, TAK1-binding protein 2; PDCD, Programmed Cell Death; IKK, IkappaB kinase. SHIP; SH2-containing inositol phosphatase 1. VSV, Vesicular somatitis virus; JNK, c-Jun N-terminal kinas; TTP, Tristetraprolin. * Corresponding author. Research Center for Immunodeficiencies, Children’s Medical Center Hospital, Dr. Qarib St, Keshavarz Blvd, Tehran 14194, Iran. Tel.: þ98 21 6692 9234; fax: þ98 21 6692 9235. E-mail address: [email protected](N. Rezaei). 0163-4453/$36 ª 2013 The British Infection Association. Published by Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.jinf.2013.07.016 www.elsevierhealth.com/journals/jinf Journal of Infection (2013) 67, 251e264
Transcript
Journal of Infection (2013) 67, 251e264
www.elsevierhealth.com/journals/jinf
REVIEW
Toll like receptor (TLR)-induced differentialexpression of microRNAs (MiRs) and immuneresponse against infection: A systematicreview
Seyed Hossein Aalaei-andabili a, Nima Rezaei a,b,c,d,*
aMolecular Immunology Research Center, Tehran University of Medical Sciences, Tehran, IranbDepartment of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, IrancResearch Center for Immunodeficiencies, Pediatrics Center of Excellence, Children’s Medical Center,Tehran University of Medical Sciences, Tehran, IrandDepartment of Infection and Immunity, School of Medicine and Biomedical Sciences, The University ofSheffield, Sheffield, UK
Accepted 6 July 2013Available online 12 July 2013
KEYWORDSMicroRNAs;Toll-like receptors;Infection
Abbreviations: LPS, lipopolysaccharidmediator for retinoid and thyroid hoSOCS4, Suppressor of cytokine signalinindependent protein kinase II; MHC IIDeath; IKK, IkappaB kinase. SHIP; SHTTP, Tristetraprolin.* Corresponding author. Research Ce
0163-4453/$36 ª 2013 The British Infehttp://dx.doi.org/10.1016/j.jinf.2013
Summary Toll like receptors (TLRs) are one of the major families of pattern recognition re-ceptors (PRRs). MicroRNAs (MiRs) are small noncoding RNAs with regulatory effects on biolog-ical process, and it has been recently shown that they can control inflammatory process andthe response to an infection by modulating the function of TLRs. In this study, we designeda systematic review to clarify the reciprocal interaction between TLRs and MiRs, in order toidentify possible future therapeutic targets and strategies. On the one hand, TLRs stimulationcan change expression level of miRs in various ways, which can lead to modulating their ef-fects. On the other hand, MiRs also influence the expression of TLRs and the intensity of theinflammatory reaction. We therefore conclude that the interaction between MiRs and TLRsis a key regulator of innate immune system. Investigations discovering therapeutic approaches
by manipulation of miRs expression level may open a new approach for the treatment of in-flammatory diseases.ª 2013 The British Infection Association. Published by Elsevier Ltd. All rights reserved.
Introduction
The innate immune system is an evolutionarily conserveddefense mechanism against pathogens, which have beendetected by the fundamental pattern recognition receptors(PRRs). Toll like receptors (TLRs) family have emerged as animportant group of PRRs.1 TLRs are fixed on the germline andcan recognize several pathogens. During bacterial, viral, andfungal invasion, danger signals are effectively detected byTLRs.2e4 TLRs are involved in inflammatory response throughendogenous ligands detection.5,6 Also, TLRs are able to bindsequences of single-stranded RNA (ssRNA) viruses on dendriticcells (DCs) and B lymphocytes, leading to inflammatory cells(including macrophage and neutrophil) activation, proinflam-matory cytokines/chemokines production, and antimicrobialpeptides synthesis.7 Till now, 13 TLRs (TLR1-TLR13) havebeen described, which each one recognizes a specific path-ogen associated molecule pattern (PAMP).8,9 Upon recogni-tion of a specific PAMP, most TLRs activate a group ofadaptor molecules. Myeloid differentiation protein 88(MyD88) and toll/interleukin 1 receptor (TIR) domain-containing adaptor inducing IFN-b (TRIF) have been reportedas twomajor adaptormolecules associated with TLRs. ExceptTLR3, all TLRs signal through the MyD88 pathway accompa-nied with TIR domain-containing adaptor protein (TI-RAP).5,9,10 These adaptor proteins lead to nucleartranslocation of transcription factors, including nuclearfactor-kappa B (NF-kB) and activator protein-1 (AP-1).11 Acti-vation of TLR, NF-kB, and AP-1 pathway leads to initiation ofhost immune system reaction against pathogens.
Recently, several endogenous feedback regulatory path-ways counter-regulating TLR signaling cascades have beendiscovered. MicroRNAs (miRs) and TLRs have reciprocaleffects, leading to controlling of inflammatory response.12
Otherwise, sustain TLR signaling may have dangerous effectson host immunity leading to autoimmune disorder, chronicinflammation, and progression of infectious disease.13
MiRs are small, noncoding RNAs, 19e24 nucleotides inlength, which regulate gene expression posttranscriptionally,by targeting the 30untranslated region (30UTR) of targetmRNAs. MiRs degrade mRNAs by RNases and inhibit theirtranslation, preventing protein synthesis.14 It has beenaccepted that miRs have determinant roles in several biolog-ical processes such as cellular development, differentiation,and adhesion.15 Also, miRs play crucial roles in developmentof hematopoietic lineage,16 proliferation of monocyte andneutrophil,17 production of type 1 interferon and inflamma-tory cytokines/chemokine,18 and immune system responsive-ness.19 These emerging evidences suggest the importance ofmiRs in regulation of both adaptive and innate immunity.
Since TLRs and miRs have critical roles in recognition ofpathogens, and immune response against invasion; under-standing their regulatory effects on inflammatory signalingcascade remains still important.20 Presentation of miRs and
TLRs, and their regulatory effects on immune system hasopened new era in the prevention and treatment of disease.In this study, we aimed to systemically review all publishedrelevant articles regarding miR and TLR controlling effect onimmune system function, suggesting possible newtherapeuticapproaches based on TLR and miR effects on immune systemsignaling pathways.
Methods and materials
Search strategy
We started our search from MEDLINE (including Pubmed andEMBASE), Scopus, and ISI web of science. Then, we performedsearches on Google Scholar; and, after finding the latestrelated article, we continued the search till the 200th unre-lated link. Also, search on Google carried out to find grayliterature. In addition, we performed searches on presentedreports in congresses using the “congress” and “conference” askey words. Moreover, backward and forward citations searchwere done by screening of all references (to identify possiblemissed studies in our search) in relevant articles. An email hasbeen sent to the first or the corresponding authors, if the fulltexts of their articles were not accessible. Non informativeabstractswere excluded, if no responsewas received after twoweeks of our email to the authors. We used terms such as“MicroRNA” or “MiRs” and “Toll like receptor” or “TLR” as keywords. There was no limitation in our search strategy.
Quality assessment of relevant studies
Critical appraisal (CA) was carried out using the Eblipcheck21 list by two of the investigators. We performedmeetings before the CA, and investigators were justifiedand trained about questions. Then, the CA has been donefor 20 selected articles and a meeting was performed as pi-lot. If there was disagreement between investigators CAscores, they discussed about, and if they did not convince,the article has been referred to the third person for re-checking. We decided to exclude all low quality articlesfrom the analysis/final report.
Inclusion and exclusion
Published articles in all languages were eligible if they metthe following criteria: 1) English, French, and Persian fulltexts or an informative abstract in English. 2) Appropriatestudy design. 3) Studies that clearly stated informationabout miRs and TLRs.
Our exclusion criteria were as follow: 1) Studies withunclear and confusing data. 2) Studies whose informationregarding miRs or TLRs regulatory effects was not properlydefined.
Table 1 Differential stimulators lead to the MicroRNAs (miRs) differential function.
MicroRNA (miR) Stimulator Effect on miR expression Effect on immune system
MiR-146 TLR Upregulation DC cross-priming inhibition24
TLR Upregulation Anti-inflammatory effect22
RNA virus infection Upregulation Inhibition of INF production90
VSV replication90
MiR-511 TLR and MRC1 Upregulation DC maturation25
MiR-155 LPS induced IL-10 Downregulation DC differentiation30
TLR, INF, and TNF Upregulation Anti-inflammatory effect47
Progesterone Downregulation Increasing of SOCS1 andanti-inflammatory effect54
MiR-16 TLR Upregulation SMRT repression and proinflammation80
MiR-101 TLR Upregulation MKP-1 targeting and proinflammation83
MiR-107 TLR Downregulation CDK6 upregulation and proinflammation88
MiR-122 Hepatitis C Downregulation Controversy (114, 115)
Differential expression of MiRs and immune response 253
Data extraction
Data extraction was completed by two of the investigatorsand then, rechecked by one of them. We extracteddemographic information of articles and all reporteddata about miRs and TLRs regulatory effects, if full textof the articles were available. Extracted data werecategorized for each miR and TLR in Microsoft OfficeExcel 2007. Informative English abstracts with non-Englishfull texts were referred to a translator to check the fulltext.
Data report
We wanted to test heterogeneity of reported results, andtherefore, perform a meta-analysis; however, since most ofthe studies were laboratory works and inappropriate forstatistical analysis, we reported them analytically withoutstatistical analysis.
Results
In initial search, 141 articles were found. Forty one articleswere only related to the organic diseases, and were
excluded. Also, 11 studies were omitted, because theywere not exactly about human immune system function. Noarticle has been excluded in quality assessment and neitherbecause of any response from authors. Finally, 89 articlesdiscussing 17 miRs in detail (Table 1) were interred to thefinal stage and were non-statistically analyzed. Kappa coef-ficient between authors was very good; Kappa: 0.9.
MiRs regulate maturation of pathogen presentingcells, controlling initiation of immune systemreaction
MiR-146a targets Notch-1, inhibiting IL-12p70 productionTwo isoforms ofmiR-146 have been recognized,miR-146a andmiR-146b, which are encoded by human chromosome 5 and10, respectively. The mature sequences of them vary only bytwo nucleotides.22 Overexpression of miR-146a in the latephase of DCmaturation can inhibit mitogen-activated proteinkinas p38 (p38MAPK), silencing expression of the IL-1, andother inflammatory markers.23 CD11b is highly expressed inDC. It has been suggested that CD11 deficiency leads to upre-gulation of TLR9 signaling, and therefore, production of IL-12p70 inDC,whichpromotesDCcross-priming of the cytotoxicT lymphocytes (CTL) activity. The CD11b stimulates TLR9
254 S.H. Aalaei-andabili, N. Rezaei
induced upregulation of miR-146a in DC through holding late-phase activation of the NF-kB. MiR-146a inhibits IL-12p70 pro-ductionby repressionofNotch-1,which ispositive regulatorofIL-12p70 secretion in wild type DC.24
MiR-511 is needed for the development of pathogenrecognition by antigen presenting cells (APCs)MiR-511 is another miR whose expression is upregulated inresponse to lipopolysacharide (LPS) stimulation in humanbloodmonocyte, DC, andmacrophage. Also, it has been foundthat miR-511 is involved in differentiation, maturation, andfunction of DC and macrophages.25 Expression of miR-511 isregulated by MRC1 genes which are present in macrophageand some DCs.26 Dicer1 activation is essential for miR synthe-sis; inhibition of the Dicer1 leads to reduction of DC-specificintercellular adhesion molecule-3-grabbing non-integrin(DCSIGN), and inversely, increasingofCD14protein level, indi-cating to themiR-511 effects on DCsmaturation.25 It has beenunderstood that miR-511 has the greatest potential to targetvarious genes necessary for DC and macrophage differentia-tion and maturation. Also, the miR can boost TLR signalingduring cell cycle arrest situations.25 However, it has been hy-pothesized that miR-511 competes with degradation factorsto increase level of target proteins.25,27
LPS induces IL-10 production to downregulate miR-155,leading to DC and macrophage maturationFollowing DC activation, miR-155 modulates the TLR/IL-1signaling axis through upregulation of SMAD pathways, andsuppressing TAK1-binding protein 2 (TAB2) and Pellino-1.23
TAB2 and Pellino-1 contain the TRAF6, leading to inflamma-tion; and their suppression downregulates the NF-kBsignaling pathway.28,29 MiR-155 expression is inverselycorrelated with p38MAPK levels, leading to the inhibitionof inflammatory genes in the late phase of the DC matura-tion.23 On the other hand, LPS can also induce IL-10, whichdownregulates miR-155 expression.30 However, in responseto miR-155 suppression, differentiation of the macrophagesand of the DCs progresses by upregulation of V-maf muscu-loaponeurotic fibrosarcoma oncogene homolog B (MafB).23
MiR-148 family impairs DCs maturation and inflammatoryresponseMiR-148 family is composed of three members: miR-148a,miR-148b, and miR-152, which play important roles in theimpairment of the innate immune response. Overexpressionof miR-148 family strikingly suppresses the secretion of IL-6,IL-12, TNF-a, and IFN-b in LPS stimulated DCs. It has beensuggested that miR-148 family is involved in maturation andfunction of DC, because expression of miR-148 familymembers increases in response to DC maturation and LPSstimulation. This miR family negatively regulates TLR medi-ated functional maturation of DC by inhibition of LPSinduced MHC II overexpression in DC, and also, suppressionof cytokine production. Further, a negative associationbetween miR-148 family and Calcium/calmodul independentprotein kinase II (CaMKII) has been recognized.31 CaMKII reg-ulates DC maturation and function, and is an importantdownstream effect of calcium which triggers TLR stimulatedproduction of proinflammatory cytokine and type IIFN.32 MiR-148 expression leads to downregulation of CaMKIIsuppressing DC maturation and function. In addition, miR-
148 upregulation results in decreasing of mature DC inducedproliferation of antigen (Ag)-specific CD4þ T cell.31
MiR-146a is responsible for establishment of endotoxintolerance and cross-toleranceMiR-146a negatively regulates proinflammatory cytokinesby targeting the 30UTRs of the TRAF6 and the IRAK-1 genes,controlling TLR signaling; however, these roles are lessdescribed for miR-146b.23 MiR-146a effects are cell type-specific.33 The expression of miR-146a is rapidly increasedin response to the IL-1b in lung alveolar epithelial cellsA549; but, miR-146a levels are not affected by LPS stimula-tion in these cells.33 MiR-146a establishes LPS and peptido-glycan (PGN) induced endotoxin tolerance and cross-tolerance in monocytes by continuous overexpression,33e35
suggesting a novel approach to desensitize cells toimproper TLR signaling pathway.33 Also, it has been hypoth-esized that miR-146a leads to the induction of RelB (NF-kBmember),35 which works as a transcription inhibitor uponbinding to the upstream promoter sequences.36 In addition,the miR supports binding of the RelB to the target pro-moter, preceding histone and DNA modifications, andtherefore suppressing acute proinflammantory genes.37
Downregulation of miR-146a does not significantly restoreendotoxin responsiveness, because RelB remains still boundto the transcriptionally silent proinflammatory promoter.However, depletion of miR-146a and RelB should be doneconcomitantly to reverse tolerance and to treat sepsis.37
Lack of miR-146a leads to increased number of functionallyimpaired regulatory T cells (Tregs), resulting in the disable-ment of immune system tolerance with massive lymphocyteactivation and tissue infiltration in various organs.38 In addi-tion to the chemical sensitivity, miR-146a can regulate me-chanically induced inflammatory cytokines in human smallairway epithelial cells (HSAECs). Pressure induced cytokinerelease is strongly dependent on NF-kB signaling pathway,indicating the importance of manipulation of miR-146alevel in controlling of the mechanically (mechanical venti-lation) induced inflammation and cytokine production.39
TLR increases miR-147 expression in both NF-kB and IRF3dependent mannersMiR-147b is the human homolog of mouse miR-147.40 Thesequence of miR-147b overlaps with the human normal mu-cosa of esophagus specific 1 (NMES1) gene. TLR2 activatesthe NF-kB; and TLR3 promotes IRF3 function, leading tothe upregulation of miR-147b; however, maximum expres-sion of miR-147b occurs by TLR4 stimulation, becauseTLR4 leads to the overexpression of the miR in both NF-kBand IRF3 dependent manners.
It has been found that miR-147b is overexpressed inalveolar macrophages secondary to LPS stimulation.41 MiR-147b acts as negative regulator of macrophage inflamma-tory response. Overexpression of miR-147b suppresses IL-6, TNF-a, and other TLR induced inflammatory cytokines,attenuating pulmonary inflammatory reaction in responseto LPS stimulation.41 These data suggest that miR-147b isan important regulator of inflammatory process, and its
Differential expression of MiRs and immune response 255
upregulation may prevent hyperinflammation of airwayepithelial cells (AECs).
MiR-155 downregulation seems to be a novel approach topreventing septic shock and allograft rejectionMiR-155 is located within the B cell integration cluster(BIC)42 that is encoded by human chromosome 21.43 The NF-kB, AP-1, and Ets are the sites involved in BIC function uponactivation of B-cell receptor (BCR).44 Function of AP-1 fam-ily components (including JunB, C-Fos, and FosB) whichhave central roles in BIC activity and induction of miR-155transcription, are dependent on extracellular signaling-regulated kinas (ERK) and c-Jun N-terminal kinas (JNK)signaling pathway.44 BACH1 is a transcriptional inhibitor,binding to the AP-1 components.45 MiR-155 rescues BACH-mediated downregulation of AP-1 signaling pathway.46
It has been found that poly ribocytidylic acid (poly(I:C))or the cytokine IFN-b induce miR-155 overexpression.47
Recently, it has been understood that TNF-a is necessaryfor IFN induced upregulation of miR-155.47,48 There is evi-dence that JNK pathway is also involved in miR-155 upregu-lation by poly(I:C), IFN, and TNF-a.47 Star type of miR-155(miR-155*) is known49 to be induced by TLR7 and JNKpathway in early phase of stimulation. KH-type splicing reg-ulatory protein (KHSRP) is responsible to promote miR-155maturation by binding to the terminal loop of miR-155 pre-cursor. Downregulation of KHSRP occurs in lack of type I IFNfunction, leading to the impairment of miR-155 maturation,and by contrast, increasing of miR-155) expression. MiR-155 negatively controls IFN-a/b and TNF-a productionthrough repressing TAB2. In contrast, miR-155) increasesIFN-a/b and TNF-a expression by targeting IRAKM.50 Also,IRAKM itself triggers TLR pathway.51 It has been suggestedthat LPS induced miR-155 overexpression is involved in sep-tic shock process; miR-155 increases the stability of TNF-amRNA and its translation, increasing susceptibility to theshock.18 LPS induced IL-10 downregulates miR-155 tran-scription from the BIC, only after TLR4 stimulation.30 IL-10 inhibitory effect is dependent on STAT352 and the pres-ence of the Ets binding site.30 IL-10 increases SH2-containing inositol phosphatase 1 (SHIP1) expression,30 sup-pressing proinflammatory response through negative regu-lation of the PIP3/Akt and NK-kB pathways.53 Also, miR-155 is regulated by progesterone as well as miR-146. Pro-gesterone downregulates both LPS and poly(I:C) inducedmiR-155 by inhibition of the NF-kB function. In contrast,progesterone promotes anti-inflammatory effects byincreasing of SOCS1 expression.54 SOCS1 has immunosup-pressive roles through inhibition of allogenic T cells prolif-eration, and promotion of Tregs generation.55 Therefore,miR-155 has been considered as responsible for allograftrejection by inhibition of SOCS1 expression.56
TLRs inhibit let-7 family expression to upregulatecytokine production promotersThe let-7 family is the first discovered miR in human,57 con-taining 9 members including (let-7a, b, c, d, e, f, g, i, andmiR-98).58 Let-7 family is involved in epithelial cell immuneresponse. Cholangiocyte (biliary epithelial cell) expresseslet-7 family, upregulating by TLR-4 stimulation. Expressionof let-7 family inhibits several immune related genes andcytokine production.59 It has been suggested that let-7
family targets CIS and SOCS4 30UTRs, suppressing their func-tions posttranscriptionally. CIS and SOCS are the proteinswhich negatively control cytokine signaling pathway. Cryp-tosporidium parvum (C. parvum) infection leads to the acti-vation of TLR signaling, and therefore, CIS proteinupregulation. Also, the infection leads to the downregula-tion of both primary and mature let-7 family miRs in aMyD88/NF-kB dependent manner.60,61 CCAAT/enhancer-binding protein b (C/EBPb) is an acute phase inflammationassociated transcription factor.62 Microbial infection formsNF-kB p50-C/EBPb silencer complex. The complex targetslet-7i promoter and deacetylates histone-H3, suppressexpression of let-7i reporter gene.63 Therefore, CIS andSOCS4 levels increase secondary to let-7 family suppres-sion. However, it seems that let-7 family plays critical rolesin cholangiocyte immune response against an invasion.59
Similar proinflammatory roles have been distinguished forlet-7 family members in bacterial infection.64
MiR-19 targets NF-kB inhibitor genesMiR-19b is a member of miR-17-92 family which differs onlyby one nucleotide from miR-19a.65 The miR has beenconsidered as responsible for most of the miR-17-92 familyeffects on NF-kB signaling pathway. MiR-19b plays proin-flammatory roles by positive regulation of NF-kB signaling.MiR-19 targets 13 genes which negatively regulate NF-kBsignaling function.66 Also, miR-19 downregulates SOCS1expression, leading to the increasing of TLR2/4 signalingand NF-kB function.67 MiR-17 is another member of miR-17-92 family, which works in opposite of miR-19. Downregu-laton of miR-19 and upregulation of miR-17 leads to thesuppression of IL-8 production level.68
MiR-21 has anti-inflammatory roles by PDCD4 suppressionLPS stimulation leads to upregulation of miR-21 in macro-phage and PBMC but not in T helper 1 (TH1) cell in MyD88and p65 (subunit of NF-kB) dependent manners. Pro-grammed cell death 4 (PDCD4) can be upregulated byTLR4 and has proinflammatory roles through inhibition ofIL-10 translation and increasing of IL-6 production.69 Also,PDCD4 targets AP-1, and therefore, suppresses tumor pro-gression.70 It has been found that miR-21 expression inhibitsNF-kB activity, and also, translation of PDCD4 mRNA.69
Thus, this miR negatively regulates inflammatory responseand increases production of anti-inflammatory IL-10.
Decorin can be used as therapeutic agentDecorin had been recognized as early response gene againstseptic inflammation. Decorin leads to reduction of miR-21expression, TGF-bproduction, and IL-10 secretion. In contrast,it leads to increased production of PDCD4, TNF-a, and IL-12 byactivating MAPK in a TLR2 and TLR4 dependent manner. Also,decorin activates NF-kB and increases activation of caspase-3.71 It seems that manipulation of miR-21 level by induction ofdecorin can be beneficial for the treatment of inflammatoryand autoimmune diseases.
Au unusual function of miR-466lIL-10 is an important regulator of immune system with anti-inflammatory roles.72 It has been reported that IL-10 degra-dation may lead to several immunological diseases.73 MiRsusually repress mRNA translation and also, lead to target
256 S.H. Aalaei-andabili, N. Rezaei
mRNA degradation; but, miR-466l has an unusual effect byincreasing IL-10 mRNA half life and protein expression.74
Tristetraprolin (TTP) is a RNA-binding protein (RBP) whichcontributes to destabilize the mRNAs of cytokines (IL-10,TNF-a, and ect).75 MiR-466l binds to the IL-10 AU-rich ele-ments (ARE) which is located in the 30UTR, and in thisway, inhibits IL-10 mRNA degradation in TLR triggeredmacrophages. Thus, miR-466l upregulates IL-10 expressionposttranscriptionally and directly by antagonizing the TTP,indicating to its crucial roles in immune systemregulation.74
MiR-210 suppress inflammatory response by p105inhibitionTLR4 stimulation leads to upregulation of HIF1-a (hypoxia-inducible factor 1-a), which is an essential promoter of miR-210 expression. Consequently, miR-210 represses the mRNAof LPS induced pro-inflammatory cytokines, including IL-6,TNF-a, and inducible nitric oxide synthase (iNOS). MiR-210targets IkB kinase b (IKK-b) downstream molecules (MyD88,TRAF6, TAK1, and TAB1) inhibiting NF-kB function. On theother hand, miR-210 abrogates the expression of p105protein (is named also NF-kB1) which is a main member oftranscription regulator family NF-kB. P105 can progress top50 and then p65, increasing NF-kB target genes.76 It is sug-gestible that miR-210 has anti-inflammatory roles by nega-tive controlling of TLR-NF-kB signaling pathway.
MiR-200b and miR-200c directly target MyD88 30UTRMiR-200 has three subtypes including miR-200a, miR-200b,and miR-200c that work as intracellular modulators of TLRinduced response.12 MiR-200b and miR-200c have commontargets; but, miR-200a acts differently.77 Initially, miR-200band miR-200c have been recognized as tumor suppressor,because these miRs target epithelial to mesenchymal transi-tion (EMT) which is an essential factor for tumor metastasisformation.78 Recently, it has been found that miR-200b andmiR-200c are expressed in TH1 cell and macrophage, playingimportant roles in innate immune response regulation. MiR-200b and miR200c interrupt TLR signaling by directly target-ing MyD88 30UTR.77 All TLRs except TLR3 work via MyD88pathway,79 this fact suggests that miR-200b and miR-200crepress NF-kB function, and consequently, attenuate inflam-matory response, inhibiting LPS induced cytokine/chemo-kine (Such as: TNF-a, CXCL9) production.77 Although it hasbeen suggested that miR-200b and miR-200c are involvedin immune homeostasis; however, strategies to manipulatetheir expression are still unknown, indicating to the neces-sity of further investigations.
NF-kB independent upregulation miR-16MiR-16 is encoded separately by two genes, which arelocated on chromosomes 13 (miR-16-1) and 3 (miR-16-2).MiR-16 levels are upregulated in LPS stimulated humanmonocytes and biliary epithelial cells in a MAPK depen-dent manner, but independently from the NF-kB pathway.MiR-16 overexpression promotes NF-kB function, and alsoleads to the increased expression of IL-6, IL-8, and IL-1aboth at the mRNA and protein levels by translationalinhibition of silencing mediator for retinoid and thyroidhormone receptor (SMRT).54 It has been reported thatSMRT 30UTR contains a binding site for miR-16, and
represses LPS stimulated NF-kB activation.80 These resultssuggest that miR-16 plays pro-inflammatory roles via posi-tive regulation of NF-kB signaling and negative controllingof SMRT.
MiR-101 targets MKP-1 and promotes inflammationTLR2, TLR3, and TLR4 can upregulate miR-101 by activationof PI3K-Akt pathway. Also, LPS stimulation leads to in-creasing of MAPK phosphatase-1 (MKP-1) expression.81 MKP-1 has regulatory effect on MAPK and negatively controlsproinflammatory cytokines secretion by deactivation ofthe MAPK.82 On the other hand, MKP-1 expression helpsthe tumor to escape from JNK1 promoted apoptosis. Incontrast, suppressed level of MKP-1 in high grade cancers,leads to more proliferation and increasing of tumormass.83 MiR-101 targets MKP-1 by binding to its 30UTR. Inhi-bition of MKP-1 function increases duration of JNK and P38phosphorylation.81 It has been suggested that glucocorti-coids (GRs) anti-inflammatory effects are based on MAPK in-hibition.84 GRs such as dexamethasone inhibit LPSstimulated PI3K-Akt pathway, leading to decreased expres-sion of miR-101, and inversely, induction of MKP-1, leadingto degradation of MAPK. Although it has been accepted thatmiR-101 promotes inflammatory response in innate immunesystem by downregulation of MKP-1; however, suggestedroles for miR-101 in tumor suppression is not clearlystated.81 Hence, further investigations are required tofind potential therapeutic effect of miR-101 expressionmanipulation. LPS suppresses miR-107, leading to increasedCDK6 and inflammation.
MiR-103 and miR-107 belong to the same miR family.MiR-103 differs only by one bp from miR-107, and they havemany common target genes.85 MiR-107 is transcribed fromthe fifth intron of pantothenate kinase 1-a (Pnak1-a)gene, which is located on murine chromosome 19.86
TLR4 can downregulate miR-107 and Pnak1-a in aMyD88-and p65 (NF-kB) dependent fashion. Also, LPS leadsto the inhibition of peroxisome proliferator-activating re-ceptor (PPAR) mRNA. PPAR is a transcription factor withanti-inflammatory effects.87 MiR-107 and Pnak1-a downre-gulation by decreased level of PPAR is highly suggested.Thus, LPS regulates miR-107 and Pnak1-a levels in MyD88-p65 (NF-kB)-PPAR dependent manners. MiR-107 negativelyregulates cyclin-dependent kinase 6 (CDK6) mRNA and pro-tein expression. CDK6 plays important proinflammatoryroles in response to LPS stimulation.88 Also, CDK6 increasescell adhesion. The suppressive effect of TLR4 on miR-107expression contributes to CDK6 upregulation, leading toimprovement of macrophage adhesion in response to LPS,increasing cell susceptibility to LPS, and therefore, impair-ment of resistance to LPS induced lethality.88
MiRs may contrast a proper immune responseagainst an infection
MiR-146a upregulation seems to be virus strategy toescape from immune responseMiR-146a plays important roles in both viral and bacterialinfection.89,90 In intestinal epithelial cells, lysosomal andproteasomal inhibitors significantly inhibit LPS inducedIRAK1 protein down-regulation but, elevated levels of the
Differential expression of MiRs and immune response 257
miR-146a in epithelial cells decrease IRAK-1 protein expres-sion, and therefore, protect the epithelium from bacteriainduced apoptosis.89 Retinoic acid-inducible gene I (RIG-I)has been recognized as a cytoplasmic detector of viralRNA.91 RIG-I deficiency in viral infected cells leads toimpairment of type I IFN production. Vesicular somatitis vi-rus (VSV) infection promotes miR-146a upregulation in mac-rophages and splenocytes by a RIG-I dependent but TLR-MyD88 independent signaling pathway. Overexpression ofmiR-146a is negatively associated with VSV stimulated pro-duction of type I IFN, proinflammatory cytokines (IL-1, IL-6,and TNF-a), and chemokines (IL-8 and RANTES) in macro-phages. Also, miR-146a upregulation, and therefore,impairment of type I IFN production promotes VSV replica-tion in macrophages, which can be mediated by manipula-tion of the miR targets such as TRAF6, IRAK1, and IRAK2.MiR-146a overexpression seems to be a new strategy for
Figure 1 MiR-146a and miR-155 act contrary in
virus to escape from the antiviral immune response andto increase virus survival. Pyrrolidine carbodithoic acid(PDTC) has been synthesized as NF-kB inhibitor which im-pairs VSV induced miR-146a upregulation.90
MiR-155 plays different roles depending on the type ofinfectionMiR-155 serves important roles in bacterial92 and viralinfection.93 TLR2 recognizes Francisella Novicida (F.N.)infection, leading to miR-155 induction in a MyD88 depen-dent manner. MiR-155 represses SHIP, and activates phos-phatidyl inositol 3-kinase (PI3K), ERK, and JNK to exertproinflammatory response against F.N. Activation of NF-kBseems to be needed for induction of miR-155 in responseto F.N infection.92,94 TLR2/4 and nucleotide-binding oligo-merization domain-containing proteins 1/2 (NOD1/2) inde-pendent induction of miR-155 has been reported in
response to Vesicular somatitis virus (VSV).
258 S.H. Aalaei-andabili, N. Rezaei
macrophage, secondary to Helicobacter pylori (H. pylori)infection. This upregulation of the miR is dependent onH. pylori type IV secretion system (T4SS), NF-kB, and AP-1 signaling pathways. It has been described that H. pyloriinduced miR-155 has antiapoptotic and chemoresistanceeffects in macrophages through inhibition of DNAdamage-induced apoptosis, and stabilization of macro-phage in a severe inflammatory environment.95 Also, miR-155 suppresses H. pylori induced IL-8 and growth relatedoncogene-a (GRO-a).96 Administration of NF-kB inhibitor(proteasome inhibitor MG132) and bafilomycin A1 (BafA1)
Figure 2 Mycobacterium tuberculosis infecti
substantially abolish miR-155 expression.95 In absence ofmiR-155, cisplatin leads to DNA damage-induced apoptosisthrough upregulation of LPIN1, PMAIP1, and TRP53INP1.97
In contrast, miR-155 has proapoptotic roles in Mycobacte-rium bovis (M. bovis) BCG infection. M. bovis/tuberculosisBCG infection leads to the phosphorylation of importantmembers of PI3K pathway. PI3K integrates with protein ki-nase C (PKC), MAPK, and NF-kB to express miR-155. Expres-sion of miR-155 increases transcription of variousproapoptotic genes including PUMA, NOXA, BID, BIM,BAK1, and SMAC.98 Thus, miR-155 expression makes
on leads to differential expression of miRs.
Differential expression of MiRs and immune response 259
macrophages and DCs more susceptible to apoptosis. Incontrast to miR-146a, overexpression of miR-155 positivelyregulates antiviral immunity (Fig. 1). MiR-155 can be ex-pressed in response to RNA virus infection in macrophagesand APCs in a RIG-I/JNK/NF-kB dependent manner.93 MiR-155 activates JAK/STAT pathway, and leads to phosporyla-tion of STATs and its translocation into nucleus.99 Conse-quently, type I IFN stimulated genes (such as: ISG15 andIP-10) will be transcribed.93 It has been reported thatSOCS1 has inhibitory effects on the activation of JAK tyro-sine kinase and phosphorylation of STAT.100 MiR-155directly targets SOCS1 expression, and subsequently pro-motes IFN signaling. Also, miR-155 suppresses VSV replica-tion.93 EpsteineBarr virus (EBV) infection can activate BICexpression via B-cell-specific factors and EBV growth-genes such as latent membrane protein 1 (LMP1) and Eps-teineBarr nuclear antigen 1 (EBNA2) which work throughNF-kB pathway. EBNA1 plays determinant role in EBVgenome maintenance during latency. It has been reportedthat miR-155 positively regulates EBNA1 expression. Also,LMP1 activates NF-kB and upregulates miR-155 to buffercontinuous stimulation of NF-kB. Debilitation of NF-kBsignaling is crucial for cell survival.101 Surprisingly, manipu-lation of miR-155 expression has been found as a noveltherapeutic approach in HIV infected patients. Activationof both TLR4 and TLR3 increase miR-155 expression in
Figure 3 LPS stimulation leads to contrary reaction of various miRsregulate various miRs; this effect of TLRs/LPS is depending on type ofare involved in LPS mediated signaling. The abbreviations of the mmitogen-activated protein kinas p38, MKP-1: MAPK phosphatase-1, SMtor, Pnak1-a: pantothenate kinas 1-a, C/EBPb: CCAAT/enhancer-bcytokine-inducible SH2 protein, HIF1-a: hypoxia inducible factor, CaMjor histocompatibility complex class II, TAB2: TAK1-binding protein 2containing inositol phosphatase 1. VSV: Vesicular somatitis virus, JN
macrophage of HIV infected patients. MiR-155 plays anti-HIV role by targeting genes, such as HIV-dependency fac-tors (HDFs), proteins involved in viral life cycle, requiredproteins for trafficking, and nuclear import of pre-integration complex of the virus. Overexpression of miR-155 leads to downregulation of HDFs (ADAM10, LEDGF,TNPO3, and Nup153 mRNAs). Also, miR-155 inhibits pre-nuclear import, leading to undetectable level of integratedvirus, and accumulation of late reverse transcriptase prod-ucts.102,103 It seems that strategies for manipulation ofmiR-155 expression may help patients to get rid of threat-ening infections.
MiR-125 and miR-155 contrary functionIt has been reported that pathogenic mycobacteria such asMycobacterium tuberculosis (M.tb) lead to lower TNF pro-duction comparing nonpathogenic mycobacteria, like Myco-bacterium smegmatis (M. smegmatis).104 Since pathogenicmycobacteria infection leads to upregulation of miR-125band nonpathogenic mycobacteria promotes miR-155 over-expression, it has been suggested that differential produc-tion of TNF originates from differential expression ofmiRs.105 MiR-125 plays important roles in response to endo-toxin shock.18 Mycobacterium tuberculosis (TB) infectionmimics LPS induced miR-125b overexpression.105 TB infec-tion contributes to envelopment of lipomannan (LM) from
. LSP stimulation can directly and indirectly upregulate or down-cells and molecules which are in the pathway. Various moleculesolecules are as following: Lps: lipopolysaccharides, p38MAPK:RT: silencing mediator for retinoid and thyroid hormone recep-
inding protein b, SOCS4: Suppressor of cytokine signaling, CIS:KII: Calcium/calmodul independent protein kinase II, MHC II: ma-, PDCD: Programmed Cell Death, IKK: IkappaB kinase. SHIP: SH2-K: c-Jun N-terminal kinas. TTP: Tristetraprolin.
260 S.H. Aalaei-andabili, N. Rezaei
most of the exposed cells. It has been found that LM canstimulate TLR2 pathway.106 Also, LM induced miR-125b in-hibits Akt signaling more than MAPK p38 signaling,105 whichare crucial for TNF production in mycobacteria infectedmacrophages.107 It has been found that miR-125b leads toless robustly and over a shorter period phosphorylation ofMAPK-activated protein kinase 2 (MK2) versus miR-155promoted phosphorylation.105 MK2 is responsible for TTPphosphorylation, and therefore, increasing stability ofTNF mRNA.108 In contrast, TB infection, and consequently,LM stimulation lead to the downregulation of miR-155b,106
leading to the reduction of TNF-a production through twofunctions; the first effect is decreasing of TNF-a mRNAhalf life,109 and the second action is upregulation ofSHIP1 expression that negatively regulates PI3K-Aktsignaling pathway.110 These results suggest that miR-125and miR-155 have opposite roles in immune system(Fig. 2), indicating to the necessity of balance between ef-fects of various miRs for a proper immune response. SincemiR-125b has antagonizing role against proinflammation,105
precise regulation of the miR expression can be used as atherapeutic strategy to control period and severity of theimmune response.
Let-7b and miR-122 are novel therapeutic agents for HCVtreatmentInterestingly, it has been found that let-7b family is apotential therapeutic regime against HCV infection.111 Let-7b significantly suppresses HCV protein expression. Also,the miR prevents persistent HCV replication, leading todecreased level of HCV RNA. It has been reported thatlet-7b binds to binding sites at the coding sequences of50-UTR and nonstructural 5B (NS5B), and therefore, physi-cally interacts with HCV RNA. These binding sites are thesame among several HCV genotypes. However, this inhibi-tory effect of let-7b on HCV replication is independent ofHCV translation suppression. In addition, let-7b upregula-tion leads to increasing of IFN-2a effects on HCV clearance.These results suggest that let-7b is an emerging therapeu-tic agent for HCV treatment.111 Since there is no reportregarding manipulation of the miR level by TLR stimulationin HCV infection, further investigations discovering aproper approach to regulate the miR expression arenecessary.
It has been found that HCV core protein can down-regulate expression of miR-122.112 Therefore, higher levelof miR-122 has been found to be associated with earlyand sustained virological response. This effect was moresignificant among patients with genotype 2 HCV infectionand IL-28B rs8099917 TT genotype.113 On the other hands,it has been reported that miR-122 is involved in HCV life cy-cle. It has been found that miR-122 antagonists strikinglydecrease HCV titres in HCV-infected patients. In contrast,miR-122 plays an anti-HBV role through inhibiting p53 onHBV transcription, suppressing HBV replication.114 Theseresults indicated to the contrary effect of miR-122 in HCVand HBV infections. Although, it is clear that miR-122 canbe used as therapeutic target in HCV infection; however,more studies are required to discover the miR precisefunction in HCV/HBV infection, leading to a proper designand delivery of the miR agonist and antagonist for HCVtreatment.
Conclusions
According to the reported results, miRs have importantroles in immune system regulation (Fig. 3). Invasions aredetected by APCs, leading to LPS stimulated immune sys-tem response. This review suggests that miR can both pro-mote and inhibit inflammatory reaction. Upregulation ofcertain miRs leads to development of innate response andproduction of cytokins, whereas, some others negativelycontrol inflammatory response to prevent excessive inflam-mation. However, proper immune response originates frombalance between various miRs. Our study suggests thatmiRs work differently, and stimulation can upregulate onemiR, and inversely, downregulate a different one. Thus,controllable expression of miR is very important to keepsafety of immune reaction and to prevent immunologicaldisease. Although studies have reported miR effects on im-munity; but, several other miR roles in association withTLRs remain yet unclear.
Altogether, investigations discovering strategies to prop-erly manipulate miR expression with attention to possibleinteractions between various miRs, and other side effectsare the most worthwhile topics.
Acknowledgments
This study was supported by a grant from the TehranUniversity of Medical Sciences (91-03-30-19098). The authorswould like to acknowledge Prof. Mihai G. Netea, Departmentof Medicine, Radboud University Nijmegen Medical Center,and Nijmegen Institute for Infection, Inflammation and Im-munity (N4i), The Netherlands; also, the authors thank Dr.Muller Fabbri, University of Southern California- Keck Schoolof Medicine, Norris Comprehensive Cancer Center, Children’sCenter for Cancer and Blood Diseases, Children’s Hospital LosAngeles, CA, USA, for critical reading of this paper.
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