title: Mutually exclusive redox forms of HMGB1 promote cell recruitment or proinflammatory cytokine release.
abstract: Tissue damage causes inflammation, by recruiting leukocytes and activating them to release proinflammatory mediators. We show that high-mobility group box 1 protein (HMGB1) orchestrates both processes by switching among mutually exclusive redox states. Reduced cysteines make HMGB1 a chemoattractant, whereas a disulfide bond makes it a proinflammatory cytokine and further cysteine oxidation to sulfonates by reactive oxygen species abrogates both activities. We show that leukocyte recruitment and activation can be separated. A nonoxidizable HMGB1 mutant in which serines replace all cysteines (3S-HMGB1) does not promote cytokine production, but is more effective than wild-type HMGB1 in recruiting leukocytes in vivo. BoxA, a HMGB1 inhibitor, interferes with leukocyte recruitment but not with activation. We detected the different redox forms of HMGB1 ex vivo within injured muscle. HMGB1 is completely reduced at first and disulfide-bonded later. Thus, HMGB1 orchestrates both key events in sterile inflammation, leukocyte recruitment and their induction to secrete inflammatory cytokines, by adopting mutually exclusive redox states.
authors.affiliation: Division of Genetics and Cell Biology, San Raffaele Scientific Institute, 20132 Milan, Italy.
authors.forename: Emilie
authors.initials: E
authors.lastname: Venereau
authors.forename: Maura
authors.initials: M
authors.lastname: Casalgrandi
authors.forename: Milena
authors.initials: M
authors.lastname: Schiraldi
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Antoine
authors.forename: Angela
authors.initials: A
authors.lastname: Cattaneo
authors.forename: Francesco
authors.initials: F
authors.lastname: De Marchis
authors.forename: Jaron
authors.initials: J
authors.lastname: Liu
authors.forename: Antonella
authors.initials: A
authors.lastname: Antonelli
authors.forename: Alessandro
authors.initials: A
authors.lastname: Preti
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Raeli
authors.forename: Sara Samadi
authors.initials: SS
authors.lastname: Shams
authors.forename: Huan
authors.initials: H
authors.lastname: Yang
authors.forename: Luca
authors.initials: L
authors.lastname: Varani
authors.forename: Ulf
authors.initials: U
authors.lastname: Andersson
authors.forename: Kevin J
authors.initials: KJ
authors.lastname: Tracey
authors.forename: Angela
authors.initials: A
authors.lastname: Bachi
authors.forename: Mariagrazia
authors.initials: M
authors.lastname: Uguccioni
authors.forename: Marco E
authors.initials: ME
authors.lastname: Bianchi
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D002465:Cell Movement / Q000187:drug effects; D002630:Chemotactic Factors / Q000378:metabolism; D003545:Cysteine / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism*; D004220:Disulfides / Q000737:chemistry / Q000378:metabolism; D024243:HMGB1 Protein / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D007249:Inflammation / Q000378:metabolism*; D007962:Leukocytes / Q000166:cytology* / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018482:Muscle, Skeletal / Q000293:injuries; D009154:Mutation; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D000911:Antibodies, Monoclonal; D002630:Chemotactic Factors; D016207:Cytokines; D004220:Disulfides; D024243:HMGB1 Protein; C104200:Hbp1 protein, rat; D017382:Reactive Oxygen Species; D011994:Recombinant Proteins; D003545:Cysteine