A soluble form of the Receptor for Advanced Glycation Endproducts (RAGE) is produced by proteolytic cleavage of the membrane bound form by the sheddase A Disintegrin and Metalloprotease 10 (ADAM10)

The receptor for advanced glycationendproducts (RAGE) mediates responses to cell dangerand stress. When bound by its many ligands (whichinclude advanced glycation endproducts, certain membersof the S100/calgranulin family, extracellular highmobilitygroup box 1, the integrin Mac-1, amyloid-peptide and fibrils), RAGE activates programs responsiblefor acute and chronic inflammation. RAGE istherefore also involved in cancer progression, diabetes,atherosclerosis, and Alzheimer’s disease. RAGE hasseveral isoforms deriving from alternative splicing,including a soluble form called endogenous secretoryRAGE (esRAGE). We show here that most solubleRAGE, either produced by cell lines or present inhuman blood, is not recognized by an anti-esRAGEantibody. Cells transfected with the cDNA for fulllengthRAGE, and thus not expressing esRAGE, producea form of soluble RAGE, cleaved RAGE (cRAGE)that derives from proteolytic cleavage of the membrane-bound molecules and acts as a decoy receptor. Byscreening chemical inhibitors and genetically modifiedmouse embryonic fibroblasts (MEFs), we identify thesheddase ADAM10 as a membrane protease responsiblefor RAGE cleavage. Binding of its ligand HMGB1promotes RAGE shedding. Our data do not disprovethe interpretation that high levels of soluble forms ofRAGE protect against chronic inflammation, but rathersuggest that they correlate with high levels of ongoinginflammation.