Leukocyte HMGB1 is required for vessel remodeling in regenerating muscles

Signals of tissue necrosis, damage-associated molecular patterns (DAMPs), cause inflammation. Leukocytes migrating into injuredtissues tonically release DAMPs, including the high mobility group box 1 protein (HMGB1). In the absence of suitable models, therelative role of DAMPs released because of necrosis or leukocyte activation has not, so far, been dissected. We have generateda mouse model lacking Hmgb1 in the hematopoietic system and studied the response to acute sterile injury of the skeletal muscle.Regenerating fibers are significantly less numerous at earlier time points and smaller at the end of the process. Leukocyte Hmgb1licenses the skeletal muscle to react to hypoxia, to express angiopoietin-2, and to initiate angiogenesis in response to injury. Vascularizationof the regenerating tissue is selectively jeopardized in the absence of leukocyte Hmgb1, revealing that it controls thenutrient and oxygen supply to the regenerating tissue. Altogether, our results reveal a novel nonredundant role for leukocyte Hmgb1in the repair of injured skeletal muscle.