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J Exp Med. 2018 Jan 2;215(1):303-318. doi: 10.1084/jem.20160217. Epub 2017 Dec 4.

High mobility group box 1 orchestrates tissue regeneration via CXCR4.

Author information

1
School of Medicine and Surgery, University of Milano-Bicocca, Milan, Italy.
2
Division of Genetics and Cell Biology, Chromatin Dynamics Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy.
3
Division of Immunology, Transplantation and Infectious Diseases, Experimental Hepatology Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy.
4
Department of Molecular Medicine, University of Pavia, Pavia, Italy.
5
Interdepartmental Centre for the Study of Biology and Sports Medicine, University of Pavia, Fondazione Salvatore Maugeri (IRCCS), Scientific Institute of Pavia, Pavia, Italy.
6
Unit of Experimental Cardio-Oncology and Cardiovascular Aging, Centro Cardiologico Monzino-IRCCS, Milan, Italy.
7
Department of Immunology and Oncology, Centro Nacional de Biotecnología/CSIC, Madrid, Spain.
8
Department of Biosciences, University of Milan, Milan, Italy.
9
The Feinstein Institute for Medical Research, Manhasset, NY.
10
Neural Stem Cell Biology Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy.
11
Institut NeuroMyogène, CNRS UMR5310, INSERM U1217, Université Lyon 1 Claude Bernard, Lyon, France.
12
INSERM U1016, Institut Cochin, CNRS, UMR8104, Université Paris Descartes, Paris, France.
13
HMGBiotech S.r.l., Milan, Italy.
14
Division of Genetics and Cell Biology, Chromatin Dynamics Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy bianchi.marco@hsr.it.
15
San Raffaele University, Milan, Italy.
16
Division of Genetics and Cell Biology, Chromatin Dynamics Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy venereau.emilie@hsr.it.

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.

PMID:
29203538
PMCID:
PMC5748844
DOI:
10.1084/jem.20160217
[Indexed for MEDLINE]
Free PMC Article

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