title: Leukocyte HMGB1 is required for vessel remodeling in regenerating muscles.
abstract: Signals of tissue necrosis, damage-associated molecular patterns (DAMPs), cause inflammation. Leukocytes migrating into injured tissues tonically release DAMPs, including the high mobility group box 1 protein (HMGB1). In the absence of suitable models, the relative role of DAMPs released because of necrosis or leukocyte activation has not, so far, been dissected. We have generated a 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 Hmgb1 licenses the skeletal muscle to react to hypoxia, to express angiopoietin-2, and to initiate angiogenesis in response to injury. Vascularization of the regenerating tissue is selectively jeopardized in the absence of leukocyte Hmgb1, revealing that it controls the nutrient and oxygen supply to the regenerating tissue. Altogether, our results reveal a novel nonredundant role for leukocyte Hmgb1 in the repair of injured skeletal muscle.
authors.affiliation: Innate Immunity and Tissue Remodeling Unit, San Raffaele Scientific Institute, 20132 Milan, Italy;
authors.forename: Lara
authors.initials: L
authors.lastname: Campana
authors.affiliation: Innate Immunity and Tissue Remodeling Unit, San Raffaele Scientific Institute, 20132 Milan, Italy;
authors.forename: Francesco
authors.initials: F
authors.lastname: Santarella
authors.affiliation: Vita-Salute, San Raffaele University, 20132 Milan, Italy; Radiology Department, Centre for Experimental Imaging, San Raffaele Scientific Institute, 20132 Milan, Italy;
authors.forename: Antonio
authors.initials: A
authors.lastname: Esposito
authors.affiliation: Autoimmunity and Vascular Inflammation Unit, San Raffaele Scientific Institute, 20132 Milan, Italy; and.
authors.forename: Norma
authors.initials: N
authors.lastname: Maugeri
authors.affiliation: Innate Immunity and Tissue Remodeling Unit, San Raffaele Scientific Institute, 20132 Milan, Italy;
authors.forename: Elena
authors.initials: E
authors.lastname: Rigamonti
authors.affiliation: Innate Immunity and Tissue Remodeling Unit, San Raffaele Scientific Institute, 20132 Milan, Italy;
authors.forename: Antonella
authors.initials: A
authors.lastname: Monno
authors.affiliation: Radiology Department, Centre for Experimental Imaging, San Raffaele Scientific Institute, 20132 Milan, Italy;
authors.forename: Tamara
authors.initials: T
authors.lastname: Canu
authors.affiliation: Vita-Salute, San Raffaele University, 20132 Milan, Italy; Radiology Department, Centre for Experimental Imaging, San Raffaele Scientific Institute, 20132 Milan, Italy;
authors.forename: Alessandro
authors.initials: A
authors.lastname: Del Maschio
authors.affiliation: Radiology Department, Centre for Experimental Imaging, San Raffaele Scientific Institute, 20132 Milan, Italy; Chromatin Dynamics Unit, San Raffaele Scientific Institute, 20132 Milan, Italy.
authors.forename: Marco E
authors.initials: ME
authors.lastname: Bianchi
authors.affiliation: Vita-Salute, San Raffaele University, 20132 Milan, Italy; Autoimmunity and Vascular Inflammation Unit, San Raffaele Scientific Institute, 20132 Milan, Italy; and.
authors.forename: Angelo A
authors.initials: AA
authors.lastname: Manfredi
authors.affiliation: Innate Immunity and Tissue Remodeling Unit, San Raffaele Scientific Institute, 20132 Milan, Italy; Vita-Salute, San Raffaele University, 20132 Milan, Italy; rovere.patrizia@hsr.it.
authors.forename: Patrizia
authors.initials: P
authors.lastname: Rovere-Querini
mesh_terms: D042702:Angiopoietin-2 / Q000235:genetics / Q000276:immunology*; D000818:Animals; D024243:HMGB1 Protein / Q000235:genetics / Q000276:immunology*; D007962:Leukocytes / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D018482:Muscle, Skeletal / Q000098:blood supply* / Q000276:immunology* / Q000293:injuries; D018919:Neovascularization, Physiologic / Q000235:genetics / Q000276:immunology*; D012038:Regeneration / Q000235:genetics / Q000276:immunology*
chemical_list: D042702:Angiopoietin-2; D024243:HMGB1 Protein; C582808:HMGB1 protein, mouse