High mobility group box 1 orchestrates tissue regeneration via CXCR4

Mario Tirone, Ngoc Lan Tran, Chiara Ceriotti, Andrea Gorzanelli, Monica Canepari, Roberto Bottinelli, Angela Raucci, Stefania Di Maggio, César Santiago, Mario Mellado, Marielle Saclier, Stéphanie François, Giorgia Careccia, Mingzhu He, Francesco De Marchis, Valentina Conti, Sabrina Ben Larbi, Sylvain Cuvellier, Maura Casalgrandi, Alessandro PretiBénédicte Chazaud, Yousef Al-Abed, Graziella Messina, Giovanni Sitia, Silvia Brunelli, Marco Emilio Bianchi, Emilie Vénéreau

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Abstract

Inflammation and tissue regeneration follow tissue damage, but little is known about how these processes are coordinated. High Mobility Group Box 1 (HMGB1) is a nuclear protein that, when released on injury, triggers inflammation. We previously showed that HMGB1 with reduced cysteines is a chemoattractant, whereas a disulfide bond makes it a proinflammatory cytokine. Here we report that fully reduced HMGB1 orchestrates muscle and liver regeneration via CXCR4, whereas disulfide HMGB1 and its receptors TLR4/MD-2 and RAGE (receptor for advanced glycation end products) are not involved. Injection of HMGB1 accelerates tissue repair by acting on resident muscle stem cells, hepatocytes, and infiltrating cells. The nonoxidizable HMGB1 mutant 3S, in which serines replace cysteines, promotes muscle and liver regeneration more efficiently than the wild-type protein and without exacerbating inflammation by selectively interacting with CXCR4. Overall, our results show that the reduced form of HMGB1 coordinates tissue regeneration and suggest that 3S may be used to safely accelerate healing after injury in diverse clinical contexts.

Original languageEnglish
Pages (from-to)303-318
Number of pages16
JournalJournal of Experimental Medicine
Volume215
Issue number1
DOIs
Publication statusPublished - Jan 2 2018

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Tirone, M., Tran, N. L., Ceriotti, C., Gorzanelli, A., Canepari, M., Bottinelli, R., Raucci, A., Di Maggio, S., Santiago, C., Mellado, M., Saclier, M., François, S., Careccia, G., He, M., De Marchis, F., Conti, V., Ben Larbi, S., Cuvellier, S., Casalgrandi, M., ... Vénéreau, E. (2018). High mobility group box 1 orchestrates tissue regeneration via CXCR4. Journal of Experimental Medicine, 215(1), 303-318. https://doi.org/10.1084/jem.20160217