Receptor for AGE (RAGE): weaving tangled webs within the inflammatory response.
The family of RAGE ligands, including Advanced Glycation Endproducts (AGEs), S100/calgranulins, High Mobility Group Box-1 (HMGB1) and amyloid beta peptide (Abeta) and beta-sheet fibrils are highly enriched in immune and inflammatory foci. In parallel, upregulation of Receptor for AGE (RAGE) is noted in diverse forms of inflammation and autoimmunity, based on experiments examining human tissues as well as animal models. Indeed, prior to the demonstration that S100/calgranulins were signal transduction ligands of RAGE, these molecules were considered "biomarkers" of disease and disease activity in disorders such as colitis and arthritis. Premiere roles for RAGE in advancing cellular migration implicate this receptor in targeting immune cells to vulnerable foci. Once engaged, ligand-RAGE interaction in inflammatory and vascular cells amplifies upregulation of inflammatory cytokines, adhesion molecules and matrix metalloproteinases (MMPs). Discerning the primal versus chronic injury-provoking roles for this ligand-receptor interaction is a challenge in delineating the functions of the ligand/RAGE axis. As RAGE is expressed by many of the key cell types linked integrally to the immune response, we propose that the sites and time course of ligand-RAGE stimulation determine the phenotype produced by this axis. Ultimately, drawing the fine line between antagonism versus stimulation of the receptor in health and disease will depend on the full characterization of RAGE in repair versus injury.
Clynes
Raphael
R
Division of Surgical Science, Department of Surgery, Columbia University Medical Center, 630 West 168th Street, P&S 17-501, New York, NY 10032, USA.
Moser
Bernhard
B
Yan
Shi Fang
SF
Ramasamy
Ravichandran
R
Herold
Kevan
K
Schmidt
Ann Marie
AM
D000818:Animals; D006801:Humans; D007249:Inflammation / Q000378:metabolism*; D008024:Ligands; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000378:metabolism*; D013312:Stress, Physiological / Q000378:metabolism; D014945:Wound Healing
D008024:Ligands; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic