RAGE mediates a novel proinflammatory axis: A central cell surface receptor for S100/calgranulin polypeptides

S100/calgranulin polypeptides are present at sites of inflammation, likely released by inflammatory cells targeted to such loci by a range of environm ental cues. We report here that receptor for AGE (RAGE) is a central cell s urface receptor for EN-RAGE (extracellular newly identified RAGE-binding pr otein) and related members of the S100/calgranulin superfamily. Interaction of EN-RAGEs with cellular RAGE on endothelium, mononuclear phagocytes, and lymphocytes triggers cellular activation, with generation of key proinflam matory mediators. Blockade of EN-RAGE/RAGE quenches delayed-type hypersensi tivity and inflammatory colitis in murine models by arresting activation of central signaling pathways and expression of inflammatory gene mediators. These data highlight a novel paradigm in inflammation and identify roles fo r EN-RAGEs and RAGE in chronic cellular activation and tissue injury.