The multiligand receptor RAGE as a progression factor amplifying immune and inflammatory responses

Abstract

The multiligand receptors that form the focus of this Perspective series have expectedly diverse functions, often conforming to potential gaps in the host response to invading pathogens that are not effectively manned by adaptive immunity. For example, the macrophage scavenger receptor (type A) interacts with bacterial cell walls and enhances clearance of Gram-negative bacteria from the circulation (1). Similarly, the macrophage mannose receptor binds mannose-rich carbohydrates typical of many microorganisms, thereby promoting their cellular uptake and disposal (2). The present contribution to the series concerns a member of the immunoglobulin superfamily that differs from the above molecules in that all known ligands in its broad repertoire can be generated endogenously (3). This cell surface protein, called RAGE because it serves as a receptor for nonenzymatically glycated adducts termed “advanced glycation endproducts” (AGEs), also binds β-sheet fibrils characteristic of amyloid; proinflammatory cytokine–like mediators of the S100/calgranulin family; and amphoterin, a nuclear protein sometimes found in the ECM (Table 1). Binding of these ligands to RAGE does not accelerate clearance or degradation but rather begins a sustained period of cellular activation mediated by receptor-dependent signaling. This is the first of several distinctive themes that have emerged from studies of RAGE. Other unusual features of the receptor include its ability to engage classes of molecules, rather than individual ligands, and its enhanced surface expression in environments rich in RAGE ligands. This last point is crucial, since it explains how upregulation of this receptor can contribute to an ascending spiral of RAGE-dependent cellular perturbation. Taken together, these features of RAGE allow the receptor to propagate cellular dysfunction in a number of pathophysiologically relevant situations, most often dictated by the formation and persistence of ligands in the tissues. As described below, these diverse situations range from the complications of diabetes and cellular perturbation in amyloidoses to immune and inflammatory responses and tumor cell behavior.