Receptor for advanced glycation endproducts: a multiligand receptor magnifying cell stress in diverse pathologic settings

Abstract

Receptor for Advanced Glycation Endproducts (RAGE) is a member of the immunoglobulin superfamily of cell surface molecules capable of interacting with a broad spectrum of ligands, including advanced glycation endproducts (AGEs), amyloid fibrils, S100/calgranulins and amphoterin. The biology of RAGE is dictated by the accumulation of these ligands at pathologic sites, leading to upregulation of the receptor and sustained RAGE-dependent cell activation eventuating in cellular dysfunction. Although RAGE is not central to the initial pathogenesis of disorders in which it ultimately appears to be involved, such as diabetes, amyloidoses, inflammatory conditions and tumors (each of these conditions leading to accumulation of RAGE ligands), the receptor functions as a progression factor driving cellular dysfunction and exaggerating the host response towards tissue destruction, rather than restitution of homeostasis. These observations suggest that RAGE might represent a therapeutic target in a diverse group of seemingly unrelated disorders linked only by a multiligand receptor with an unusually wide and diverse repertoire of ligands, namely, RAGE.

Introduction

Multiligand receptors are an intriguing group of cell surface structures whose broad repertoire of ligands defies simple classification with respect to structural or functional properties. Examples of such receptors include Receptor for Advanced Glycation Endproducts (RAGE) [1], CD36 [2], scavenger receptor-B1 (SR-B1) [3], type A scavenger receptor [4], [5], [6] and Low Density Lipoprotein Receptor-Related protein (LRP) [7]. RAGE, an immunoglobulin superfamily molecule, is a particularly striking member of this family [8]. Its ligands include products of nonenzymatic glycoxidation (advanced glycation endproducts or AGEs) [9], the amyloid-β (Aβ) peptide cleavage product of β-amyloid precursor protein [10], the S100/calgranulin family of proinflammatory cytokine-like mediators [11], and the high mobility group 1 DNA binding protein amphoterin [12], [13]. RAGE biology is largely dictated by the expression or accumulation of its ligands. Thus, in mature animals, there is little expression of RAGE in most tissues, whereas deposition of ligands triggers receptor expression [10], [14], [15], [16]. For example, there are few cortical neurons which express RAGE in the central nervous system of mature animals under homeostatic conditions [14]. However, during development, when high levels of amphoterin are present in the central nervous system, RAGE is increased in a wide range of cortical neurons [12]. Similarly, when pathogenic Aβ species accumulate in Alzheimer’s disease, RAGE expression increases in neurons, microglia and affected cerebral vasculature. In contrast to the suppression of receptor expression observed with the Low Density Lipoprotein (LDL) receptor in a lipoprotein-rich environment [17], RAGE is upregulated by its ligands. This mechanism provides the potential for exacerbating cellular dysfunction due to RAGE–ligand interaction, as increasing expression of the receptor allows for more profound RAGE-mediated induction of cellular dysfunction.

This review of RAGE biology will summarize progress in understanding the contribution of the receptor to the biology of tumors, inflammatory disorders, amyloidoses and diabetic complications. In each case, the relevant ligands/disorders include S100 proteins (tumors), S100 proteins, amphoterin and AGEs (inflammation), amyloid fibrils and S100 proteins (amyloidoses), and AGEs and S100 proteins (diabetic complications).