jo ur nal home p age: www.elsev ier .com/ locate /mol imm
eview
AGE and TLRs: Relatives, friends or neighbours?
aridatul Aini Ibrahima,b,c, Carol L. Armoura, Simon Phippsd, Maria B. Sukkara,b,∗
Woolcock Institute of Medical Research, Sydney Medical School, The University of Sydney, NSW 2006, AustraliaSchool of Pharmacy, The University of Technology, Sydney, NSW 2007, AustraliaDepartment of Pharmacology, Faculty of Medicine, University of Malaya, Kuala Lumpur 50603, MalaysiaSchool of Biomedical Sciences and Australian Infectious Diseases Research Centre, The University of Queensland, Queensland 4072, Australia
r t i c l e i n f o
rticle history:eceived 2 July 2013ccepted 8 July 2013vailable online 14 August 2013
eywords:eceptor for advanced glycation endroducts (RAGE)igh mobility group box-1 (HMGB1)100 proteins
a b s t r a c t
The innate immune system forms the first line of protection against infectious and non-infectious tissueinjury. Cells of the innate immune system detect pathogen-associated molecular patterns or endogenousmolecules released as a result of tissue injury or inflammation through various innate immune recep-tors, collectively termed pattern-recognition receptors. Members of the Toll-like receptor (TLR) family ofpattern-recognition receptors have well established roles in the host immune response to infection, whilethe receptor for advanced glycation end products (RAGE) is a pattern-recognition receptor predominantlyinvolved in the recognition of endogenous molecules released in the context of infection, physiologicalstress or chronic inflammation. RAGE and TLRs share common ligands and signaling pathways, and accu-mulating evidence points towards their co-operative interaction in the host immune response. At present
however, little is known about the mechanisms that result in TLR versus RAGE signalling or RAGE–TLRcross-talk in response to their shared ligands. Here we review what is known in relation to the physico-chemical basis of ligand interactions between TLRs and RAGE, focusing on three shared ligands of thesereceptors: HMGB1, S100A8/A9 and LPS. Our aim is to discuss what is known about differential ligandinteractions with RAGE and TLRs and to highlight important areas for further investigation so that wemay better understand the role of these receptors and their relationship in host defense.
. Introduction
RAGE and TLRs play a critical role in the innate immune sys-em as they can recognize and interact with microbial productsi.e. pathogen-associated molecular patterns or PAMPs) as wells endogenous molecules released in the context of tissue injurynd inflammation (i.e. damage-associated molecular patterns orAMPs). Ligation of RAGE and TLR signalling results in the acti-ation of immune and inflammatory responses involved in hostefence (Botos et al., 2011; Chang, 2010).
Recently, it has been suggested that RAGE and some membersf the TLR family functionally interact to coordinate and regulate
mmune and inflammatory responses. RAGE co-operation with cer-ain TLRs results in amplification of inflammatory responses andhere is increasing evidence to support their potential synergism.
Abbreviations: CpG-A, class A cytosine-guanine-rich; DAMP, damage-associatedolecular pattern; HMGB1, high mobility group box-1; LPS, lipopolysaccharides;
AMP, pathogen-associated molecular pattern; PRR, pattern recognition receptor;AGE, receptor for advanced glycation end products; TLR, Toll-like receptor.∗ Corresponding author at: School of Pharmacy, The University of Technology,
RAGE and TLRs share several common ligands including HMGB1(Hori et al., 1995; Huttunen et al., 2002; Ivanov et al., 2007; Jordanaand Evdokia, 2012; Liu et al., 2009; Park et al., 2004; Yang et al.,2010a; Yang et al., 2012), the S100A8/A9 heterodimeric proteincomplex (Turovskaya et al., 2008; Vogl, 2007), the bacterial cellwall component LPS (Visintin et al., 2003; Yamamoto et al., 2011)and �-sheet fibrils like serum amyloid A (Cheng et al., 2008; Yanet al., 2000) and amyloid � (Deane et al., 2003; Udan et al., 2008;Yan et al., 1996; Yan et al., 1998). RAGE also appears to interactwith TIRAP and MyD88, both of which are intracellular adaptorproteins used by TLRs to activate downstream signalling pathways(Hreggvidsdottir et al., 2009; Ivanov et al., 2007; Qin et al., 2009;Sakaguchi et al., 2011; Tian et al., 2007).
So far, much of the evidence in the literature relating to RAGEand TLR co-operation or synergy has focused on signalling path-ways down-stream of these receptors and the outcome of theseinteractions on the inflammatory response. However, understand-ing of the mechanism of RAGE–TLR cross-talk at the receptorlevel is extremely limited and important questions remain to beaddressed – particularly whether RAGE–TLR synergy is due to
physical association of the receptors. Here we discuss what isknown about the structural and biochemical basis of ligand inter-actions with RAGE and TLRs, with a view to highlighting possiblemechanisms of RAGE and TLR co-operation at the receptor level
740 Z.A. Ibrahim et al. / Molecular Immunology 56 (2013) 739– 744
Table 1Summary of RAGE and TLRs interaction with their common ligands.
Ligands Receptors Affinity Important feature mediating the interaction
HMGB1 RAGE (Hori et al., 1995; Huttunen et al., 2002;Jordana and Evdokia, 2012; Liu et al., 2009)
5–10 nM RAGE V-domain and C-terminal of HMGB1B-box domain
TLR4 (Yang et al., 2010b; Yang et al., 2012) 1.5–22 �M Cys23 and Cys45 disulphide bond and reducedCys106 within HMGB1 structure
TLR2 and TLR9 (Ivanov et al., 2007; Park et al.,2004)
Not determined Not determined
S100A8/A9 complex RAGE (Turovskaya et al., 2008) 34.4 ± 13 nM RAGE N-glycansTLR4 (Vogl, 2007) 1.1–2.5 × 10−8 M S100A8 protein and MD2/TLR4 complex
fat
1
mtatCubf
iTmdl1(
2
2
nptHilte
lsoutgbalbioai
LPS RAGE (Yamamoto et al., 2011)
TLR4 (Visintin et al., 2003)
or future investigation. We have focused the discussion on RAGEnd TLR interactions with three of their shared ligands: HMGB1,he S100A8/A9 protein complex and LPS (summarized in Table 1).
.1. RAGE and TLRs structure at a glance
The receptor for advanced glycation end products (RAGE) is aember of the immunoglobulin superfamily of cell surface recep-
ors. Its structure consists of an extracellular domain comprised ofn N-terminal sequence and three Ig-like regions including one V-ype domain and two C-type domains, C1 and C2. The V-type and1-domains are joined together forming an integrated structuralnit important for ligand recognition. RAGE has a single transmem-rane domain and a short cytoplasmic domain which is essentialor signal transduction (Dattilo et al., 2007; Fritz et al., 2010).
TLRs are a group of type 1 transmembrane proteins consist-ng of ten identified members in humans (TLR1 through to TLR10).heir structures are comprised of an extracellular domain, a trans-embrane domain and a cytoplasmic domain. The extracellular
omain contains leucine-rich repeat (LRR) motifs that mediateigand recognition, while the cytoplasmic domain contains Toll/IL-
receptor (TIR) domain which is important for signal transductionBotos et al., 2011; Chang, 2010).
. RAGE and TLR interactions with their shared ligands
.1. HMGB1
HMGB1 is a DNA binding protein which is released from theucleus during tissue injury, infection and inflammation. Severalost-translational modifications such as acetylation, phosphoryla-ion, methylation and poly (ADP) – ribosylation are required forMGB1 nuclear-cytoplasmic translocation and its ultimate release
nto the extracellular environment (Stros, 2010). In the extracellu-ar space, HMGB1 activates immune and inflammatory responseshrough binding to a number of receptors including RAGE and sev-ral members of the TLR family (Hori et al., 1995; Yu et al., 2006).
The first evidence demonstrating HMGB1 as a RAGE bindingigand came from a study by Hori et al. who were at the timeearching for RAGE ligands in bovine lung extracts. After a seriesf sequencing studies with proteins isolated by a RAGE affinity col-mn, it was revealed that the binding protein was HMGB1. Sincehen, the HMGB1-RAGE interaction has been validated by radioli-and binding assays which demonstrated HMGB1-RAGE binding toe specific, saturable, dose-dependent and of higher affinity thandvanced glycation end-products (AGEs), the first reported RAGEigands (Hori et al., 1995). Further insight into the physicochemicalasis of the HMGB1-RAGE interaction has come from recent stud-
es which show that the binding is mediated through the V-domainf RAGE and the C-terminal of the HMGB1 B-box domain (aminocids position 150–183). The negatively charged RAGE V-domainnteracts with the positively charged acidic residues located in the
∼35 nM RAGE V-domainNot determined Lys128 and Lys132 within MD2 structure
C-terminal region of HMGB1 leading to the formation of a sta-ble ligand-receptor complex (Fritz, 2011; Huttunen et al., 2002;Jordana and Evdokia, 2012; Liu et al., 2009). More recently, a studyhas shown that the RAGE-HMGB1 interaction also depends on hep-aran sulfate, a cell-surface proteoglycan. RAGE and heparan sulfatereadily form a complex at the cell surface prior to HMGB1 bindingand the presence of HMGB1 further increases RAGE-heparan sul-fate association as a result of receptor complex stabilization. Thisfinding has shed new light on the critical role of heparan sulfatein mediating the interaction between HMGB1 and RAGE (Xu et al.,2011).
A group of researchers from Protelica and Bio3 Researchare developing a novel protein scaffold-based inhibitor usingfibronectin type III domain, a polypeptide made up of a smallmonomeric �-sandwich protein. This molecule (called R2F8), nowpatented in several countries, has been demonstrated to inhibitHMGB1-RAGE interactions in vitro in a dose-dependent manner.Current efforts are aimed at extending its biological half-life sothat it can be used to disrupt HMGB1-RAGE interactions in vivo.If successfully developed, this molecule will expand the opportu-nity to further explore HMGB1-RAGE interactions in disease models(Universal Fibronectin Type III Binding Domain Libraries, PatentApplication, Protelica and Bio3 Research).
While HMGB1 has also been reported to signal via a number ofTLRs, including TLR2, TLR4 and TLR9, very little is known about thephysicochemical mechanism of binding between HMGB1 and thesereceptors (Hreggvidsdottir et al., 2012; Ivanov et al., 2007; Parket al., 2004; van Zoelen et al., 2009). HMGB1 binding to TLR4 andHMGB1-mediated cytokine activity depend on specific redox modi-fications within the HMGB1 molecule; specifically a disulfide bondbetween Cys23 and Cys45 and reduced Cys106 (thiol). However,under different molecular states where all cysteine residues arefully reduced, HMGB1 loses its TLR4-binding ability. Fully reducedHMGB1 function as a chemoattractant but the receptor pathwaysmediating its chemotactic activity are yet to be identified (Yanget al., 2010b; Yang et al., 2012). While there is evidence demon-strating that reducible HMGB1 can bind to RAGE, this interaction isnot associated with HMGB1 chemoattractive function (Tang et al.,2010). Moreover, carboxylated glycans such as heparan sulfate mayplay an important role in mediating the HMGB1-RAGE interaction,although it is not known whether this is the case with respectto HMGB1-TLR interactions (Xu et al., 2011). Further studies areneeded to explore HMGB1-TLR binding mechanisms, and particu-larly charaterization of the TLR binding region(s) within the HMGB1molecule.
Interestingly, a number of TLR ligands such as the extracellu-lar DNA material class A cytosine-guanine-rich (CpG-A)-DNA andthe bacterial cell wall component lipopolysaccharide (LPS) form
complexes with HMGB1. These complexes elicit stronger inflam-matory responses compared to HMGB1 or the partner moleculealone via mechanisms that appear to involve co-activation of TLRand RAGE signalling (Hreggvidsdottir et al., 2009; Qin et al., 2009;
Z.A. Ibrahim et al. / Molecular Immunology 56 (2013) 739– 744 741
Fig. 1. HMGB1 binding to its receptors. (A) HMGB1 binds to RAGE in the presence of the cell surface proteoglycan heparan sulfate. The complex formation between RAGE,HMGB1 and heparan sulfate induces the activation of cellular signaling which ultimately results in cell migratory responses. (B) HMGB1 can also interact with TLRs such asT ith TLl underc
Tiettdmd
puBlrvkwHdo
2
SpC
LR2, TLR4 and TLR9 to induce cytokine release. (C) HMGB1 can form complexes wigand and this elicits stronger inflammatory responses. However, the mechanismross-talk.
ian et al., 2007). A recent study excluded RAGE-TLR cooperationn the inflammatory response induced by HMGB1 complexes withither the TLR4 ligand LPS or the TLR2 ligand Pam3CSK4, showinghat this is mediated only by the activation of TLR2 or −4, respec-ively (Hreggvidsdottir et al., 2012). However, since this was onlyetermined at the signalling level, structural studies using nuclearagnetic or surface plasmon resonance assays will be necessary to
efinitively exclude a role for RAGE (Fig. 1).Finally, while we have some information regarding the
hysiochemical basis of HMGB1-RAGE/TLR interactions in vitro,nderstanding of their interaction in vivo remains extremely vague.ecause HMGB1 interacts with multiple receptors, this obviously
imits the use of receptor gene knockout mice to discern HMGB1-eceptor interactions in immune and inflammatory responses inivo. One approach to address this would be to employ doublenockout mice (e.g. RAGE-TLR4 deficient mice) or another approachould be to conduct parallel studies that employ recombinantMGB1 molecules lacking the TLR-binding site or RAGE-bindingomain in their structure to allow specific interaction with onlyne receptor.
.2. S100A8/A9
S100A8 and S100A9 are members of the S100 protein family.100 proteins interact with various effector molecules in the cyto-lasm following binding of Ca2+ or other elements such as Zn2+ oru2+ via the helix-loop-helix structural domain known as EF-hand
R ligands such as PAM3CSK4, a TLR2 agonist; LPS, a TLR4 ligand and CpG-A, a TLR9lying this is not well understood, especially with respect to the role of RAGE–TLR
motifs. Extracellular release has been demonstrated for S100A8and S100A9 protein, which are secreted in a heterodimeric formby activated immune cells such as monocytes, granulocytes andneutrophils (Altwegg et al., 2007). The extracellular S100A8/A9 pro-tein complex serves as an alarmin, triggering immune responsesby engaging with pattern-recognition receptors such as RAGE andTLR4.
S100A8/A9 heterodimeric complexes have been identified asligands of RAGE in a co-immunoprecipitation study in isolatedcardiac myocytes from mice (Boyd et al., 2008). In this study,tissue lysates containing S100A8 and S100A9 proteins wereimmunoprecipitated with specific antibodies against both pro-teins and the immunoprecipitated proteins were separated byelectrophoresis and probed with anti-RAGE antibodies. RAGE co-immunoprecipitated with S100A8 and S100A9 proteins in thetissue lysates, demonstrating a strong interaction between RAGEand these proteins.
Although there have been several studies reporting thatS100A8/A9 protein interacts with RAGE, many of them focus onlyon the signalling pathways, for instance activation of kinases likep38 MAPK and transcription factors such as NF-�B, as well as down-stream cellular effects following the S100A8/A9-RAGE interactionrather than ligand-receptor recognition and binding (Gebhardt
et al., 2006; Ghavami et al., 2008; Hermani et al., 2006). However,accumulating evidence suggests that N-glycans present in RAGE,which in this case is a carboxylated glycan, is important in mediat-ing their ligand-receptor binding. This is in agreement with earlier
7 r Imm
sagc2itKtca
spKstpigl
SotTtSwb
iTtwhiap(Smaa2miFgi
2
bpLTmLCaTt(i
42 Z.A. Ibrahim et al. / Molecula
tudies that demonstrate S100A8/A9 proteins bind to carboxylatednd other modified glycans such as heparan sulfate glycosamino-lycans expressed on the surface of chondrocytes and endothelialells (Robinson et al., 2002; Srikrishna et al., 2001; van Lent et al.,008b). A study by Turovskaya and colleagues further character-
zed the S100A8/A9-RAGE binding interaction by demonstratinghat S100A8/A9 protein directly binds immobilized RAGE with ad of 34.4 ± 13 nM. The presence of glycans is required to mediate
heir ligand-receptor interaction as deglycosylation of RAGE (a pro-ess that eliminates glycans from the receptor) almost completelybolished S100A8/A9 binding (Turovskaya et al., 2008).
S100A8/A9 is also an endogenous ligand for TLR4. In an in vitrourface plasmon resonance study, it was demonstrated that thisrotein complex binds directly to TLR4 with a binding affinity ofd 1.1–2.5 × 10−8 M (Vogl, 2007). The interaction was found to bepecifically mediated via S100A8 binding to MD2, a component ofhe TLR4 signalling complex. Further evidence that the S100A8/A9rotein signals via TLR4 come from studies which show that block-
ng TLR4 with a small molecule inhibitor such as TAK-242 or usingene knockout mice almost completely suppress S100A8/A9 cellu-ar responses (Schelbergen et al., 2012; van Lent et al., 2008a).
Despite evidence for TLR4 as a signalling receptor for the100A8/A9 complex, little is known about the physiochemical basisf this ligand-receptor interaction. Structural studies are neededo characterize the physicochemical interaction, and to identifyLR-binding sites in the heterodimeric structure of S100A8/A9 pro-ein. Furthermore, since glycans seem to be essential in mediating100A8/A9 binding to RAGE, it is also important to investigatehether glycans expressed on TLR4 also mediate ligand-receptor
inding between S100A8/A9 protein and TLR4.Of note, a recent in vitro study directly compared the S100A8/A9
nteraction with TLR4 and RAGE and found that RAGE but notLR4 associates with S100A8/A9 protein in colon tumour cells, buthe mechanisms underlying this selective ligand-receptor bindingere not determined (Ichikawa et al., 2011). RAGE has a three-foldigher binding affinity to S100A8/A9 protein than TLR4 suggest-
ng this may be one factor, but it is also possible that bindingnd preferential activation of specific receptors depends on theathophysiological conditions, cell type and ligand concentrationsTurovskaya et al., 2008; Vogl, 2007). Indeed, there is evidence that100A8/A9 interaction with RAGE is associated with inflammation-ediated carcinogenesis whereas its interaction with TLR4 is
ssociated with inflammatory processes in autoimmune disordersnd infection (Schelbergen et al., 2012; van Lent et al., 2008a; Vogl,007). However, there is a study which shows that TLR4-deficientice are protected against S100A8/A9-induced tumours, suggest-
ng this is not so clear cut (Fukata et al., 2007; Hiratsuka, 2008).urther studies are needed to determine whether there is conver-ence between RAGE and TLR4 in response to S100A8/A9 proteinn different pathophysiological conditions.
.3. Lipopolysaccharides (LPS)
LPS, the major constituent of the cell wall of Gram-negativeacteria is composed of polysaccharides attached to a lipid com-onent known as lipid A, which mediates its biological activity.PS was first demonstrated to signal via TLR4 in the late 1990s.he evidence came from a study using C3H/HeJ and C57BL/10ScCRice which were observed to be insensitive to the effects of
PS. Inquiry into the genetic basis revealed that C3H/HeJ and57BL/10ScCR mice had a single point mutation in the TLR4 genet amino acid residue 712 (pro712his) or a complete absence of
LR4 mRNA expression (Poltorak et al., 1998). Consistent withhese results, TLR4-deficient mice also failed to respond to LPS,Hoshino et al., 1999), while a potent synthetic lipid A antagonistnhibited TLR4-mediated NF-�B activation and subsequent cellular
unology 56 (2013) 739– 744
responses in vitro (Chow et al., 1999). Structural and biochemi-cal analyses have demonstrated that several molecules, includingLPS binding protein (LBP), glycoprotein CD14 and an extracellu-lar adaptor protein MD2 are all required to assist LPS transfer andrecognition by TLR4. MD2 binds to TLR4 on the cell surface beforeLPS binding takes place and this binding occurs via extracellularleucine–rich repeats in TLR4 (Visintin et al., 2003). CD14, togetherwith the lipid transfer molecule, LBP, then bring LPS into closeproximity and facilitates LPS transfer to the pre-formed TLR4-MD2complex (da Silva Correia et al., 2001; Jiang et al., 2000). LPS specif-ically interacts with MD2 via positive amino acid residues (Lys 128and 132) in the MD2 structure, leading to the formation a stablecomplex, which in turn promotes TLR4 aggregation and activationof the receptor.
There is evidence to suggest that the 3D-conformation ofthe LPS molecule determines the receptor binding and associ-ated cellular responses. LPS with conically shaped lipid A derivedfrom Escherichia coli and Salmonella spp. binds TLR4, inducingstrong inflammatory responses. Interestingly, however, cylindri-cally shaped lipid A derived from several bacteria including P.gingivalis can bind and activate TLR2, but induces less potentinflammatory responses (Netea et al., 2002). Indeed, while somestudies have shown that LPS interacts with TLR2, it is not clearwhether this plays an important role in the biological response toLPS in vivo (Beutler, 2000; da Silva Correia et al., 2001; Hirschfeldet al., 2000).
Of note, recent studies demonstrate that LPS can also interactwith RAGE. Using surface plasmon resonance assays, it was shownthat LPS isolated from E. coli can bind directly to RAGE with a meanKd of ∼35 nM (Yamamoto et al., 2011). The binding was furtherconfirmed in a plate competition assay and LPS was found to dosedependently and competitively inhibit the binding of another RAGEligand, AGE-BSA to the receptor. LPS associates with RAGE throughthe V-domain of the RAGE ligand-binding domain, and interest-ingly, this interaction does not require other partner molecules as isthe case with TLR4. Importantly, LPS binding to RAGE induced sim-ilar cellular responses as that seen with TLR4 binding both in vitroand in vivo. While it is unknown whether TLR4 and RAGE cooperatewith each other in response to LPS or whether only one receptor isactivated at one time, a study demonstrates that LPS when in com-plex with another ligand such as HMGB1, requires co-activation ofboth RAGE and TLR4 (Qin et al., 2009).
3. Conclusion and future perspectives
It is clear from the evidence at hand, that common TLR/RAGEligands may bind preferentially to one receptor versus the otherunder certain physiological or pathological conditions, but thefactor(s) which determine this – be it the cell type, ligand con-centration or molecular state of the ligand or receptor is stilllargely unknown. Certainly, structural and biochemical studieshave guided us towards a better understanding of the physico-chemical basis mediating RAGE and TLR interactions with theirligands. However, examination of the current literature exposessignificant gaps in knowledge. That is, to what extent do the physio-chemical properties of pathogen- or damage-associated molecularpatterns determine their preferential interaction with TLRs versusRAGE; and by the same token, to what extent do physiochemicalproperties of RAGE and TLRs promote selective or co-interactionwith their common ligands.
Moving forward, there is much that is still yet to be donein terms of understanding TLR and RAGE interactions with their
common ligands, and the mechanisms of their cross-talk or syn-ergy when engaged by common ligands. Specifically, the factorsthat allow discrimination or promote collaboration between RAGEand TLR signalling need to be determined. It is not until we have
r Imm
aooafis
tsfamo
R
A
B
B
B
C
C
C
d
D
D
F
F
F
G
G
H
H
H
H
H
Z.A. Ibrahim et al. / Molecula
chieved this that it will be possible to fully understand the rolef these receptors in homeostasis and host defence. While muchf the research to date has focussed on the signalling pathwaysctivated down-stream of TLR/RAGE ligation, future efforts in thiseld should focus on the physiochemical determinants of TLR/RAGEignalling under both physiological and pathological conditions.
Further biochemical and structural studies are clearly necessaryo uncover TLR and RAGE binding regions within the moleculartructure of their common and distinct ligands. This would assisturther elucidation of unresolved RAGE- or TLR-ligand interactionsnd provide new direction for pharmacological interventions thatay discriminate between these receptor pathways in the context
f certain diseases.
eferences
ltwegg, L.A., Neidhart, M., Hersberger, M., Müller, S., Eberli, F.R., Corti, R., Roffi,M., Sütsch, G., Gay, S., von Eckardstein, A., Wischnewsky, M.B., Lüscher, T.F.,Maier, W., 2007. Myeloid-related protein 8/14 complex is released by mono-cytes and granulocytes at the site of coronary occlusion: a novel, early, andsensitive marker of acute coronary syndromes. European Heart Journal 28,941–948.
eutler, B., 2000. TLR4: central component of the sole mammalian LPS sensor. Cur-rent Opinion in Immunology 12, 20–26.
otos, I., Segal David, M., Davies David, R., 2011. The structural biology of Toll-likereceptors. Structure (London, England: 1993) 19, 447–459.
oyd, J.H., Kan, B., Roberts, H., Wang, Y., Walley, K.R., 2008. S100A8 and S100A9 medi-ate endotoxin-induced cardiomyocyte dysfunction via the receptor for advancedglycation end products. Circulation Research 102, 1239–1246.
hang, Z.L., 2010. Important aspects of Toll-like receptors, ligands and their signalingpathways. Inflammation Research 59, 791–808.
heng, N., He, R., Tian, J., Ye, P.P., Ye, R.D., 2008. Cutting edge: TLR2 is a functionalreceptor for acute-phase serum amyloid A. The Journal of Immunology 181,22–26.
a Silva Correia, J., Soldau, K., Christen, U., Tobias, P.S., Ulevitch, R.J., 2001.Lipopolysaccharide is in close proximity to each of the proteins in its membranereceptor complex: transfer from CD14 to TLR4 and MD-2. Journal of BiologicalChemistry 276, 21129–21135.
attilo, B.M., Fritz, G., Leclerc, E., Vander Kooi, C.W., Heizmann, C.W., Chazin,W.J., 2007. The extracellular region of the receptor for advanced glycation endproducts is composed of two independent structural units. Biochemistry 46,6957–6970.
eane, R., Du Yan, S., Submamaryan, R.K., LaRue, B., Jovanovic, S., Hogg, E., Welch, D.,Manness, L., Lin, C., Yu, J., Zhu, H., Ghiso, J., Frangione, B., Stern, A., Schmidt, A.M.,Armstrong, D.L., Arnold, B., Liliensiek, B., Nawroth, P., Hofman, F., Kindy, M.,Stern, D., Zlokovic, B., 2003. RAGE mediates amyloid-[beta] peptide transportacross the blood-brain barrier and accumulation in brain. Nature Medicine 9,907–913.
ritz, G., 2011. RAGE: a single receptor fits multiple ligands. Trends in BiochemicalSciences 36, 625–632.
ritz, G., Botelho, H.M., Morozova-Roche, L.A., Gomes, C.M., 2010. Natural and amy-loid self-assembly of S100 proteins: structural basis of functional diversity. FEBSJournal 277, 4578–4590.
ukata, M., Chen, A., Vamadevan, A.S., Cohen, J., Breglio, K., Krishnareddy, S., Hsu, D.,Xu, R., Harpaz, N., Dannenberg, A.J., Subbaramaiah, K., Cooper, H.S., Itzkowitz,S.H., Abreu, M.T., 2007. Toll-like receptor-4 promotes the development of colitis-associated colorectal tumors. Gastroenterology 133, 1869–1881.
ebhardt, C., Németh, J., Angel, P., Hess, J., 2006. S100A8 and S100A9 in inflammationand cancer. Biochemical Pharmacology 72, 1622–1631.
havami, S., Rashedi, I., Dattilo, B.M., Eshraghi, M., Chazin, W.J., Hashemi, M., Wes-selborg, S., Kerkhoff, C., Los, M., 2008. S100A8/A9 at low concentration promotestumor cell growth via RAGE ligation and MAP kinase-dependent pathway. Jour-nal of Leukocyte Biology 83, 1484–1492.
ermani, A., de Servi, B., Medunjanin, S., Tessier, P.A., Mayer, D., 2006. S100A8 andS100A9 activate MAP kinase and NF-�B signaling pathways and trigger translo-cation of RAGE in human prostate cancer cells. Experimental Cell Research 312,184–197.
iratsuka, S., 2008. The S100A8-serum amyloid A3-TLR4 paracrine cascade estab-lishes a pre-metastatic phase. Nature Cell Biology 10, 1349–1355.
irschfeld, M., Ma, Y., Weis, J.H., Vogel, S.N., Weis, J.J., 2000. Cutting edge: repurifica-tion of lipopolysaccharide eliminates signaling through both human and murineToll-like receptor 2. The Journal of Immunology 165, 618–622.
ori, O., Brett, J., Slattery, T., Cao, R., Zhang, J., Chen, J.X., Nagashima, M., Lundh, E.R.,
Vijay, S., Nitecki, D., Morser, J., Stern, D., Schmidt, A.M., 1995. The receptor foradvanced glycation end products (RAGE) is a cellular binding site for amphoterin.Journal of Biological Chemistry 270, 25752–25761.
hyporesponsive to lipopolysaccharide: evidence for TLR4 as the lps gene prod-uct. The Journal of Immunology 162, 3749–3752.
Hreggvidsdottir, H.S., Lundberg, A.M., Aveberger, A.C., Klevenvall, L., Andersson,U., Harris, H.E., 2012. High mobility group box protein 1 (HMGB1)-partnermolecule complexes enhance cytokine production by signaling through thepartner molecule receptor. Molecular Medicine 18, 224–230.
Hreggvidsdottir, H.S., Östberg, T., Wähämaa, H., Schierbeck, H., Aveberger, A.-C.,Klevenvall, L., Palmblad, K., Ottosson, L., Andersson, U., Harris, H.E., 2009. Thealarmin HMGB1 acts in synergy with endogenous and exogenous danger signalsto promote inflammation. Journal of Leukocyte Biology 86, 655–662.
Huttunen, H.J., Fages, C., Kuja-Panula, J., Ridley, A.J., Rauvala, H., 2002. Receptor foradvanced glycation end products-binding COOH-terminal motif of amphoterininhibits invasive migration and metastasis. Cancer Research 62, 4805–4811.
Ichikawa, M., Williams, R., Wang, L., Vogl, T., Srikrishna, G., 2011. S100A8/A9 activatekey genes and pathways in colon tumor progression. Molecular Cancer Research9, 133–148.
Jiang, Q., Akashi, S., Miyake, K., Petty, H.R., 2000. Cutting edge: lipopolysaccharideinduces physical proximity between CD14 and Toll-like receptor 4 (TLR4) priorto nuclear translocation of NF-�B. Journal of Immunology 165, 3541–3544.
Jordana, T., Evdokia, P., 2012. High mobility group B1 protein interacts with itsreceptor RAGE in tumor cells but not in normal tissues. Oncology letters 3,214–218.
Liu, R., Mori, S., Wake, H., Zhang, J., Liu, K., Izushi, Y., Takahashi, H.K., Peng, B., Nishi-bori, M., 2009. Establishment of in vitro binding assay of high mobility groupbox-1 and S100A12 to receptor for advanced glycation endproducts: heparin’seffect on binding. Acta Medica Okayama 63, 203–211.
Netea, M.G., van Deuren, M., Kullberg, B.J., Cavaillon, J.-M., Van der Meer, J.W.M.,2002. Does the shape of lipid A determine the interaction of LPS with Toll-likereceptors? Trends in Immunology 23, 135–139.
Park, J.S., Svetkauskaite, D., He, Q., Kim, J.-Y., Strassheim, D., Ishizaka, A., Abraham,E., 2004. Involvement of Toll-like receptors 2 and 4 in cellular activation by highmobility group box 1 protein. Journal of Biological Chemistry 279, 7370–7377.
Poltorak, A., He, X., Smirnova, I., Liu, M.-Y., Huffel, C.V., Du, X., Birdwell, D., Alejos,E., Silva, M., Galanos, C., Freudenberg, M., Ricciardi-Castagnoli, P., Layton, B.,Beutler, B., 1998. Defective LPS signaling in C3H/HeJ and C57BL/10ScCr mice:mutations in TLR4 gene. Science 282, 2085–2088.
Qin, Y.-H., Dai, S.-M., Tang, G.-S., Zhang, J., Ren, D., Wang, Z.-W., Shen, Q., 2009.HMGB1 enhances the proinflammatory activity of lipopolysaccharide by pro-moting the phosphorylation of MAPK p38 through receptor for advancedglycation end products. The Journal of Immunology 183, 6244–6250.
Robinson, M.J., Tessier, P., Poulsom, R., Hogg, N., 2002. The S100 family heterodimer,MRP-8/14, binds with high affinity to heparin and heparan sulfate glycosamino-glycans on endothelial cells. Journal of Biological Chemistry 277, 3658–3665.
Sakaguchi, M., Murata, H., Yamamoto, K.-i., Ono, T., Sakaguchi, Y., Motoyama, A.,Hibino, T., Kataoka, K., Huh, N.-h., 2011. TIRAP, an adaptor protein for TLR2/4,transduces a signal from RAGE phosphorylated upon ligand binding. PLoS ONE6, e23132.
Schelbergen, R.F.P., Blom, A.B., van den Bosch, M.H.J., Slöetjes, A., Abdollahi-Roodsaz,S., Schreurs, B.W., Mort, J.S., Vogl, T., Roth, J., van den Berg, W.B., van Lent,P.L.E.M., 2012. Alarmins S100A8 and S100A9 elicit a catabolic effect in humanosteoarthritic chondrocytes that is dependent on Toll-like receptor 4. Arthritisand Rheumatism 64, 1477–1487.
Srikrishna, G., Panneerselvam, K., Westphal, V., Abraham, V., Varki, A., Freeze, H.H.,2001. Two proteins modulating transendothelial migration of leukocytes recog-nize novel carboxylated glycans on endothelial cells. The Journal of Immunology166, 4678–4688.
Stros, M., 2010. HMGB proteins: interactions with DNA and chromatin. Biochimicaet Biophysica Acta (BBA) – Gene Regulatory Mechanisms 1799, 101–113.
Tang, D., Kang, R., Cheh, C.W., Livesey, K.M., Liang, X., Schapiro, N.E., Benschop, R.,Sparvero, L.J., Amoscato, A.A., Tracey, K.J., Zeh, H.J., Lotze, M.T., 2010. HMGB1release and redox regulates autophagy and apoptosis in cancer cells. Oncogene29, 5299–5310.
Tian, J., Avalos, A.M., Mao, S.-Y., Chen, B., Senthil, K., Wu, H., Parroche, P., Drabic,S., Golenbock, D., Sirois, C., Hua, J., An, L.L., Audoly, L., La Rosa, G., Bierhaus,A., Naworth, P., Marshak-Rothstein, A., Crow, M.K., Fitzgerald, K.A., Latz, E.,Kiener, P.A., Coyle, A.J., 2007. Toll-like receptor 9-dependent activation byDNA-containing immune complexes is mediated by HMGB1 and RAGE. NatureImmunology 8, 487–496.
Turovskaya, O., Foell, D., Sinha, P., Vogl, T., Newlin, R., Nayak, J., Nguyen, M., Olsson, A.,Nawroth, P.P., Bierhaus, A., Varki, N., Kronenberg, M., Freeze, H.H., Srikrishna, G.,2008. RAGE, carboxylated glycans and S100A8/A9 play essential roles in colitis-associated carcinogenesis. Carcinogenesis 29, 2035–2043.
Udan, M.L.D., Ajit, D., Crouse, N.R., Nichols, M.R., 2008. Toll-like receptors 2 and 4mediate A�(1-42) activation of the innate immune response in a human mono-cytic cell line. Journal of Neurochemistry 104, 524–533.
van Lent, P.L.E.M., Grevers, L., Blom, A.B., Sloetjes, A., Mort, J.S., Vogl, T., Nacken, W.,van den Berg, W.B., Roth, J., 2008a. Myeloid-related proteins S100A8/S100A9
regulate joint inflammation and cartilage destruction during antigen-inducedarthritis. Annals of the Rheumatic Diseases 67, 1750–1758.
van Lent, P.L.E.M., Grevers, L.C., Blom, A.B., Arntz, O.J., van de Loo, F.A.J., van der Kraan,P., Abdollahi-Roodsaz, S., Srikrishna, G., Freeze, H., Sloetjes, A., Nacken, W., Vogl,T., Roth, J., van den Berg, W.B., 2008b. Stimulation of chondrocyte-mediated
of cysteine residues regulates the cytokine activity of high mobility group box-1
44 Z.A. Ibrahim et al. / Molecula
cartilage destruction by S100A8 in experimental murine arthritis. Arthritis andRheumatism 58, 3776–3787.
an Zoelen, M.A.D., Yang, H., Florquin, S., Meijers, J.C.M., Akira, S., Arnold, B.,Nawroth, P.P., Bierhaus, A., Tracey, K.J., Poll, T.v.d., 2009. Role of Toll-likereceptors 2 and 4, and the receptor for advanced glycation end products inhigh-mobility group box 1-induced inflammation in vivo. Shock 31, 280–284,http://dx.doi.org/10.1097/SHK.0b013e318186262d.
isintin, A., Latz, E., Monks, B.G., Espevik, T., Golenbock, D.T., 2003. Lysines 128 and132 enable lipopolysaccharide binding to MD-2, leading to Toll-like receptor-4 aggregation and signal transduction. Journal of Biological Chemistry 278,48313–48320.
ogl, T., 2007. Mrp8 and Mrp14 are endogenous activators of Toll-like receptor 4,promoting lethal, endotoxin-induced shock. Nature Medicine 13, 1042–1049.
u, D., Young, J., Song, D., Esko, J.D., 2011. Heparan sulfate is essential for high mobil-ity group protein 1 (HMGB1) signaling by the receptor for advanced glycationend products (RAGE). Journal of Biological Chemistry 286, 41736–41744.
amamoto, Y., Harashima, A., Saito, H., Tsuneyama, K., Munesue, S., Motoyoshi, S.,Han, D., Watanabe, T., Asano, M., Takasawa, S., Okamoto, H., Shimura, S., Kara-sawa, T., Yonekura, H., Yamamoto, H., 2011. Septic shock is associated withreceptor for advanced glycation end products ligation of LPS. The Journal of
Immunology 186, 3248–3257.
an, S.D., Chen, X., Fu, J., Chen, M., Zhu, H., Roher, A., Slattery, T., Zhao, L., Nagashima,M., Morser, J., Migheli, A., Nawroth, P., Stern, D., Schmidt, A.M., 1996. RAGEand amyloid-[beta] peptide neurotoxicity in Alzheimer’s disease. Nature 382,685–691.
unology 56 (2013) 739– 744
Yan, S.D., Stern, D., Kane, M.D., Kuo, Y.-M., Lampert, H.C., Rohe, A.E., 1998. RAGE-ABinteractions in the pathophysiology of Alzheimer’s disease. Restorative Neurol-ogy and Neuroscience 12, 167–173.
Yan, S.D., Zhu, H., Zhu, A., Golabek, A., Du, H., Roher, A., Yu, J., Soto, C., Schmidt,A.M., Stern, D., Kindy, M., 2000. Receptor-dependent cell stress and amyloidaccumulation in systemic amyloidosis. Nature Medicine 6, 643–651.
Yang, H., Hreggvidsdottir, H., Palmblad, K., Wang, H., Ochani, M., Li, J., Lu, B., Cha-van, S., Rosas-Ballina, M., Al-Abed, Y., Akira, S., Bierhaus, A., Erlandsson-Harris,H., Andersson, U., Tracey, K., 2010a. A critical cysteine is required for HMGB1binding to Toll-like receptor 4 and activation of macrophage cytokine release.Proceedings of the National Academy of Sciences of the United States of America107, 11942–11947.
Yang, H., Hreggvidsdottir, H.S., Palmblad, K., Wang, H., Ochani, M., Li, J., Lu, B., Cha-van, S., Rosas-Ballina, M., Al-Abed, Y., Akira, S., Bierhaus, A., Erlandsson-Harris,H., Andersson, U., Tracey, K.J., 2010b. A critical cysteine is required for HMGB1binding to Toll-like receptor 4 and activation of macrophage cytokine release.Proceedings of the National Academy of Sciences 107, 11942–11947.
