The Receptor for Advanced Glycation End Products (RAGE) Is a Cellular Binding Site for Amphoterin

Abstract

The receptor for advanced glycation end products (RAGE), a newly-identified member of the immunoglobulin superfamily, mediates interactions of advanced glycation end product (AGE)-modified proteins with endothelium and other cell types. Survey of normal tissues demonstrated RAGE expression in situations in which accumulation of AGEs would be unexpected, leading to the hypothesis that under physiologic circumstances, RAGE might mediate interaction with ligands distinct from AGEs. Sequential chromatography of bovine lung extract identified polypeptides with M r values of Ϸ12,000 (p12) and Ϸ23,000 (p23) which bound RAGE. NH 2 -terminal and internal protein sequence data for p23 matched that reported previously for amphoterin. Amphoterin purified from rat brain or recombinant rat amphoterin bound to purified sRAGE in a saturable and dose-dependent manner, blocked by anti-RAGE IgG or a soluble form of RAGE (sRAGE). Cultured embryonic rat neurons, which express RAGE, displayed dose-dependent binding of 125 I-amphoterin which was prevented by blockade of RAGE using antibody to the receptor or excess soluble receptor (sRAGE). A functional correlate of RAGE-amphoterin interaction was inhibition by anti-RAGE F(ab) 2 and sRAGE of neurite formation by cortical neurons specifically on amphoterin-coated substrates. Consistent with a potential role for RAGEamphoterin interaction in development, amphoterin and RAGE mRNA/antigen were co-localized in developing rat brain. These data indicate that RAGE has physiologically relevant ligands distinct from AGEs which are likely, via their interaction with the receptor, to participate in physiologic processes outside of the context of diabetes and accumulation of AGEs.Incubation of proteins or lipids with aldose sugars results in nonenzymatic glycation and oxidation (1-7). Following formation of the reversible early glycation products, Schiff bases and Amadori products, further complex molecular rearrangements result in irreversible advanced glycation end products (AGEs). 1Factors favoring nonenzymatic glycation include delayed protein turnover, as in amyloidoses, accumulation of macromolecules with high lysine content, and situations with elevated glucose levels, as in diabetes. AGE formation occurs during normal aging, and at an accelerated rate in diabetes, in which their accumulation in the plasma and vessel wall has been speculated to underlie the pathogenesis of vasculopathy (1, 2, 4).One of the principal means through which AGEs impact on cellular elements is through interaction with cellular binding proteins. Although there are several possible cell-associated polypeptides with which AGEs might interact (8, 9), our work has focussed on the receptor for AGEs (RAGE), as its expression in endothelium, vascular smooth muscle, mononuclear phagocytes, and the central nervous system suggests strategic loci for interaction with the glycated ligands (10, 11). The potential pathophysiologic relevance of AGE-RAGE interaction was emphasized by studies demonstrating that blockade of RAGE pr...

Requirement of HMGB1 and RAGE for the maturation of human plasmacytoid dendritic cells

“…4). A similar role for RAGE in mediating HMGB1 functional activities has been demonstrated in different models, including regeneration of peripheral nerves [38,62] and tumor growth/metastasis [63].…”

“…In addition, recombinant HMGB1 induced a low production of IFN-a by PDC. The best characterized receptor for HMGB1 on inflammatory cells is RAGE [38,40]. We observed that freshly isolated PDC express RAGE, which makes them potentially responsive to HMGB1 (Fig.…”

“…HMGB1 reaches the extracellular environment when monocytes/macrophages actively secrete it following acetylation and transfer to secretory endolysosomal compartments [34][35][36] or by passive release from necrotic cells [37]. Once in the extracellular milieu, HMGB1 has been shown to activate the receptor for advanced glycation end-products (RAGE) [38][39][40] and possibly TLR2 in neutrophils and macrophages [41]. Extracellular HMGB1 mediates endotoxin lethality and inflammation [32,[42][43][44][45][46].…”

“…3D, p<0.05). HMGB1 is a specific ligand for RAGE, the best characterized receptor for HMGB1 on hematopoietic cells [38]. We checked if this receptor is present on the plasma membrane of PDC.…”

Translating Lung Function Genome-Wide Association Study (GWAS) Findings

“…AGER encodes RAGE, a multiligand receptor implicated in homeostasis, development, inflammation and diseases including diabetes, Alzheimer's and COPD (Bierhaus & Nawroth, 2009;Cheng et al, 2013;Ferhani et al, 2010;Hofmann et al, 2002;Hori et al, 1995;Sparvero et al, 2009;Wu, Ma, Nicholson, & Black, 2011;Yan et al, 1996). Associations were also identified for GPR126 encoding an adhesion G protein coupled receptor, whilst Interestingly, SNPs in HHIP and HTR4 were found to be significantly associated with both FEV1 and FEV1/FVC.…”