title: A novel pathway of HMGB1-mediated inflammatory cell recruitment that requires Mac-1-integrin.
abstract: High-mobility group box 1 (HMGB1) is released extracellularly upon cell necrosis acting as a mediator in tissue injury and inflammation. However, the molecular mechanisms for the proinflammatory effect of HMGB1 are poorly understood. Here, we define a novel function of HMGB1 in promoting Mac-1-dependent neutrophil recruitment. HMGB1 administration induced rapid neutrophil recruitment in vivo. HMGB1-mediated recruitment was prevented in mice deficient in the beta2-integrin Mac-1 but not in those deficient in LFA-1. As observed by bone marrow chimera experiments, Mac-1-dependent neutrophil recruitment induced by HMGB1 required the presence of receptor for advanced glycation end products (RAGE) on neutrophils but not on endothelial cells. In vitro, HMGB1 enhanced the interaction between Mac-1 and RAGE. Consistently, HMGB1 activated Mac-1 as well as Mac-1-mediated adhesive and migratory functions of neutrophils in a RAGE-dependent manner. Moreover, HMGB1-induced activation of nuclear factor-kappaB in neutrophils required both Mac-1 and RAGE. Together, a novel HMGB1-dependent pathway for inflammatory cell recruitment and activation that requires the functional interplay between Mac-1 and RAGE is described here.
authors.affiliation: Experimental Immunology Branch, NCI, NIH, Bethesda, MD 20892, USA.
authors.forename: Valeria V
authors.initials: VV
authors.lastname: Orlova
authors.forename: Eun Young
authors.initials: EY
authors.lastname: Choi
authors.forename: Changping
authors.initials: C
authors.lastname: Xie
authors.forename: Emmanouil
authors.initials: E
authors.lastname: Chavakis
authors.forename: Angelika
authors.initials: A
authors.lastname: Bierhaus
authors.forename: Eveliina
authors.initials: E
authors.lastname: Ihanus
authors.forename: Christie M
authors.initials: CM
authors.lastname: Ballantyne
authors.forename: Carl G
authors.initials: CG
authors.lastname: Gahmberg
authors.forename: Marco E
authors.initials: ME
authors.lastname: Bianchi
authors.forename: Peter P
authors.initials: PP
authors.lastname: Nawroth
authors.forename: Triantafyllos
authors.initials: T
authors.lastname: Chavakis
mesh_terms: D000818:Animals; D002448:Cell Adhesion / Q000502:physiology; D002478:Cells, Cultured; D002633:Chemotaxis / Q000502:physiology; D024202:Electrophoretic Mobility Shift Assay; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D017127:Glycation End Products, Advanced; D024243:HMGB1 Protein / Q000378:metabolism*; D006801:Humans; D007249:Inflammation / Q000378:metabolism* / Q000503:physiopathology; D016169:Lymphocyte Function-Associated Antigen-1 / Q000235:genetics; D016177:Macrophage-1 Antigen / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D016328:NF-kappa B / Q000378:metabolism; D020556:Neutrophil Infiltration / Q000502:physiology*; D009504:Neutrophils / Q000378:metabolism* / Q000502:physiology; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000235:genetics / Q000378:metabolism
chemical_list: D017127:Glycation End Products, Advanced; D024243:HMGB1 Protein; D016169:Lymphocyte Function-Associated Antigen-1; D016177:Macrophage-1 Antigen; D016328:NF-kappa B; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic