Journal - The FASEB Journal

Abstract :

The receptor for advanced glycation endproducts (RAGE) mediatesresponses to cell danger and stress. When bound by its manyligands (which include advanced glycation endproducts, certainmembers of the S100/calgranulin family, extracellular high-mobilitygroup box 1, the integrin Mac-1, amyloid ß-peptide andfibrils), RAGE activates programs responsible for acute andchronic inflammation. RAGE is therefore also involved in cancerprogression, diabetes, atherosclerosis, and Alzheimer’sdisease. RAGE has several isoforms deriving from alternativesplicing, including a soluble form called endogenous secretoryRAGE (esRAGE). We show here that most soluble RAGE, either producedby cell lines or present in human blood, is not recognized byan anti-esRAGE antibody. Cells transfected with the cDNA forfull-length RAGE, and thus not expressing esRAGE, produce aform of soluble RAGE, cleaved RAGE (cRAGE) that derives fromproteolytic cleavage of the membrane-bound molecules and actsas a decoy receptor. By screening chemical inhibitors and geneticallymodified mouse embryonic fibroblasts (MEFs), we identify thesheddase ADAM10 as a membrane protease responsible for RAGEcleavage. Binding of its ligand HMGB1 promotes RAGE shedding.Our data do not disprove the interpretation that high levelsof soluble forms of RAGE protect against chronic inflammation,but rather suggest that they correlate with high levels of ongoinginflammation.—Raucci, A., Cugusi, S., Antonelli, A., Barabino,S. M., Monti, L., Bierhaus, A., Reiss, K., Saftig, P., Bianchi,M. E. A soluble form of the receptor for advanced glycationendproducts (RAGE) is produced by proteolytic cleavage of themembrane-bound form by the sheddase a disintegrin and metalloprotease10 (ADAM10).