Mutually exclusive redox forms of HMGB1 promote cell recruitment or proinflammatory cytokine release

Venereau, Emilie; Casalgrandi, Maura; Schiraldi, Milena; Antoine, Daniel J.; Cattaneo, Angela; De Marchis, Francesco; Liu, Jaron; Antonelli, Antonella; Preti, Alessandro; Raeli, Lorenzo; Samadi Shams, Sara; Yang, Huan; Varani, Luca; Andersson, Ulf; Tracey, Kevin J.; Bachi, Angela; Uguccioni, Mariagrazia; Bianchi, Marco E.

doi:10.1084/jem.20120189

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Journal article

Mutually exclusive redox forms of HMGB1 promote cell recruitment or proinflammatory cytokine release

Venereau, Emilie Division of Genetics and Cell Biology, San Raffaele Scientific Institute, 20132 Milan, Italy
Casalgrandi, Maura HMGBiotech Srl, 20133 Milan, Italy
Schiraldi, Milena Institute for Research in Biomedicine (IRB), Faculty of Biomedical Sciences, Università della Svizzera italiana, Switzerland
Antoine, Daniel J. Medical Research Council Centre for Drug Safety Science, Department of Molecular and Clinical Pharmacology, University of Liverpool, Liverpool L69 3BX, England, UK
Cattaneo, Angela Division of Genetics and Cell Biology, San Raffaele Scientific Institute, 20132 Milan, Italy
De Marchis, Francesco Division of Genetics and Cell Biology, San Raffaele Scientific Institute, 20132 Milan, Italy
Liu, Jaron San Raffaele University, 20132 Milan, Italy
Antonelli, Antonella San Raffaele University, 20132 Milan, Italy
Preti, Alessandro HMGBiotech Srl, 20133 Milan, Italy
Raeli, Lorenzo Institute for Research in Biomedicine (IRB), Faculty of Biomedical Sciences, Università della Svizzera italiana, Switzerland
Samadi Shams, Sara San Raffaele University, 20132 Milan, Italy
Yang, Huan Feinstein Institute for Medical Research, Manhasset, NY 11030
Varani, Luca Institute for Research in Biomedicine (IRB), Faculty of Biomedical Sciences, Università della Svizzera italiana, Switzerland
Andersson, Ulf Departments of Women’s and Children’s Health, Karolinska Institute and Karolinska University Hospital, SE-171 77 Stockholm, Sweden
Tracey, Kevin J. Feinstein Institute for Medical Research, Manhasset, NY 11030
Bachi, Angela Division of Genetics and Cell Biology, San Raffaele Scientific Institute, 20132 Milan, Italy
Uguccioni, Mariagrazia Institute for Research in Biomedicine (IRB), Faculty of Biomedical Sciences, Università della Svizzera italiana, Switzerland
Bianchi, Marco E. Division of Genetics and Cell Biology, San Raffaele Scientific Institute, 20132 Milan, Italy - San Raffaele University, 20132 Milan, Italy

06.08.2012

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The journal of experimental medicine. - 2012, vol. 209, no. 9, p. 1519-1528

English 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.

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