Elsevier

Molecular Immunology

Volume 56, Issue 4, 31 December 2013, Pages 739-744
Molecular Immunology

Review
RAGE and TLRs: Relatives, friends or neighbours?

https://doi.org/10.1016/j.molimm.2013.07.008Get rights and content

Highlights

  • RAGE and TLRs play a critical role in host defence.

  • Mechanisms of their discriminate or co-interaction with common ligands are unknown.

  • Understanding of their cross-talk or synergy in cellular responses is also poor.

  • The physiochemical basis of RAGE/TLR-ligand interactions needs investigation.

Abstract

The innate immune system forms the first line of protection against infectious and non-infectious tissue injury. Cells of the innate immune system detect pathogen-associated molecular patterns or endogenous molecules released as a result of tissue injury or inflammation through various innate immune receptors, collectively termed pattern-recognition receptors. Members of the Toll-like receptor (TLR) family of pattern-recognition receptors have well established roles in the host immune response to infection, while the receptor for advanced glycation end products (RAGE) is a pattern-recognition receptor predominantly involved in the recognition of endogenous molecules released in the context of infection, physiological stress or chronic inflammation. RAGE and TLRs share common ligands and signaling pathways, and accumulating 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–TLR cross-talk in response to their shared ligands. Here we review what is known in relation to the physicochemical basis of ligand interactions between TLRs and RAGE, focusing on three shared ligands of these receptors: HMGB1, S100A8/A9 and LPS. Our aim is to discuss what is known about differential ligand interactions with RAGE and TLRs and to highlight important areas for further investigation so that we may 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 system as they can recognize and interact with microbial products (i.e. pathogen-associated molecular patterns or PAMPs) as well as endogenous molecules released in the context of tissue injury and inflammation (i.e. damage-associated molecular patterns or DAMPs). Ligation of RAGE and TLR signalling results in the activation of immune and inflammatory responses involved in host defence (Botos et al., 2011, Chang, 2010).

Recently, it has been suggested that RAGE and some members of the TLR family functionally interact to coordinate and regulate immune and inflammatory responses. RAGE co-operation with certain TLRs results in amplification of inflammatory responses and there is increasing evidence to support their potential synergism. RAGE and TLRs share several common ligands including HMGB1 (Hori et al., 1995, Huttunen et al., 2002, Ivanov et al., 2007, Jordana and Evdokia, 2012, Liu et al., 2009, Park et al., 2004, Yang et al., 2010a, Yang et al., 2012), the S100A8/A9 heterodimeric protein complex (Turovskaya et al., 2008, Vogl, 2007), the bacterial cell wall component LPS (Visintin et al., 2003, Yamamoto et al., 2011) and β-sheet fibrils like serum amyloid A (Cheng et al., 2008, Yan et al., 2000) and amyloid β (Deane et al., 2003, Udan et al., 2008, Yan et al., 1996, Yan et al., 1998). RAGE also appears to interact with TIRAP and MyD88, both of which are intracellular adaptor proteins 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 RAGE and TLR co-operation or synergy has focused on signalling pathways down-stream of these receptors and the outcome of these interactions on the inflammatory response. However, understanding of the mechanism of RAGE–TLR cross-talk at the receptor level is extremely limited and important questions remain to be addressed – particularly whether RAGE–TLR synergy is due to physical association of the receptors. Here we discuss what is known about the structural and biochemical basis of ligand interactions with RAGE and TLRs, with a view to highlighting possible mechanisms of RAGE and TLR co-operation at the receptor level for future investigation. We have focused the discussion on RAGE and TLR interactions with three of their shared ligands: HMGB1, the S100A8/A9 protein complex and LPS (summarized in Table 1).

The receptor for advanced glycation end products (RAGE) is a member of the immunoglobulin superfamily of cell surface receptors. Its structure consists of an extracellular domain comprised of an N-terminal sequence and three Ig-like regions including one V-type domain and two C-type domains, C1 and C2. The V-type and C1-domains are joined together forming an integrated structural unit important for ligand recognition. RAGE has a single transmembrane domain and a short cytoplasmic domain which is essential for signal transduction (Dattilo et al., 2007, Fritz et al., 2010).

TLRs are a group of type 1 transmembrane proteins consisting of ten identified members in humans (TLR1 through to TLR10). Their structures are comprised of an extracellular domain, a transmembrane domain and a cytoplasmic domain. The extracellular domain contains leucine-rich repeat (LRR) motifs that mediate ligand recognition, while the cytoplasmic domain contains Toll/IL-1 receptor (TIR) domain which is important for signal transduction (Botos et al., 2011, Chang, 2010).

Section snippets

HMGB1

HMGB1 is a DNA binding protein which is released from the nucleus during tissue injury, infection and inflammation. Several post-translational modifications such as acetylation, phosphorylation, methylation and poly (ADP) – ribosylation are required for HMGB1 nuclear-cytoplasmic translocation and its ultimate release into the extracellular environment (Štros, 2010). In the extracellular space, HMGB1 activates immune and inflammatory responses through binding to a number of receptors including

Conclusion and future perspectives

It is clear from the evidence at hand, that common TLR/RAGE ligands may bind preferentially to one receptor versus the other under certain physiological or pathological conditions, but the factor(s) which determine this – be it the cell type, ligand concentration or molecular state of the ligand or receptor is still largely unknown. Certainly, structural and biochemical studies have guided us towards a better understanding of the physicochemical basis mediating RAGE and TLR interactions with

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