Physiological and pathophysiological outcomes of the interactions of HMGB1 with cell surface receptors.
Extracellularly occurring HMGB1, either released during cell injury or actively secreted from cells, has profound effects on behaviour of a wide variety of cell types. Extracellular HMGB1 regulates migratory responses of many cell types, including neuron and growth cone migration, invasive migration of tumour cells, and migration of endothelial and immune cells. RAGE (Receptor for Advanced Glycation End Products) plays a key role as a cell surface receptor in most, if not all HMGB1-dependent migration mechanisms. HMGB1 binds to the distal immunoglobulin-like domain of RAGE, activating a signalling pathway that ends up in modulation of the cytoskeleton for regulation of cell motility. In addition to RAGE, proteoglycans and sulfated carbohydrate epitopes of glycolipids and glycoproteins may play a role as cell surface binding sites of HMGB1, affecting migratory behaviour of cells. In addition to physiological and pathophysiological cell migration control, HMGB1 has been widely studied as a molecule linking tissue injury to inflammatory mechanisms. HMGB1 by itself has little if any proinflammatory activity but it appears to activate innate immunity mechanisms as a complex with DNA, lipids and/or proinflammatory cytokines. The inflammation-inducing activity of HMGB1/DNA complexes may depend on both RAGE and Toll-like receptors of the immune cell surface. In addition to the receptors activating innate immunity, receptors downregulating inflammation upon HMGB1 release have been recently found, and include thrombomodulin and the CD-24/Siglec pathway.
Rauvala
Heikki
H
Neuroscience Center, P.O. Box 56, FIN-00014, University of Helsinki, Finland. heikki.rauvala@helsinki.fi
Rouhiainen
Ari
A
D000818:Animals; D002465:Cell Movement; D004194:Disease; D024243:HMGB1 Protein / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D007249:Inflammation / Q000378:metabolism / Q000473:pathology; D011509:Proteoglycans / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000378:metabolism*
D024243:HMGB1 Protein; D011509:Proteoglycans; D011956:Receptors, Cell Surface