title: Monocyte/Macrophage-derived IGF-1 Orchestrates Murine Skeletal Muscle Regeneration and Modulates Autocrine Polarization.
abstract: Insulin-like growth factor 1 (IGF-1) is a potent enhancer of tissue regeneration, and its overexpression in muscle injury leads to hastened resolution of the inflammatory phase. Here, we show that monocytes/macrophages constitute an important initial source of IGF-1 in muscle injury, as conditional deletion of the IGF-1 gene specifically in mouse myeloid cells (ϕIGF-1 CKO) blocked the normal surge of local IGF-1 in damaged muscle and significantly compromised regeneration. In injured muscle, Ly6C+ monocytes/macrophages and CD206+ macrophages expressed equivalent IGF-1 levels, which were transiently upregulated during transition from the inflammation to repair. In injured ϕIGF-1 CKO mouse muscle, accumulation of CD206+ macrophages was impaired, while an increase in Ly6C+ monocytes/macrophages was favored. Transcriptional profiling uncovered inflammatory skewing in ϕIGF-1 CKO macrophages, which failed to fully induce a reparative gene program in vitro or in vivo, revealing a novel autocrine role for IGF-1 in modulating murine macrophage phenotypes. These data establish local macrophage-derived IGF-1 as a key factor in inflammation resolution and macrophage polarization during muscle regeneration.
authors.affiliation: Mouse Biology Unit, European Molecular Biology Laboratory (EMBL), Monterotondo, Rome, Italy; National Heart and Lung Institute, Imperial College London, London, UK. Electronic address: j.tonkin@imperial.ac.uk.
authors.forename: Joanne
authors.initials: J
authors.lastname: Tonkin
authors.affiliation: Mouse Biology Unit, European Molecular Biology Laboratory (EMBL), Monterotondo, Rome, Italy; Current address: Department of Pathology, Maastricht University (CARIM), Maastricht, The Netherlands.
authors.forename: Lieve
authors.initials: L
authors.lastname: Temmerman
authors.affiliation: National Heart and Lung Institute, Imperial College London, London, UK.
authors.forename: Robert D
authors.initials: RD
authors.lastname: Sampson
authors.affiliation: National Heart and Lung Institute, Imperial College London, London, UK.
authors.forename: Enrique
authors.initials: E
authors.lastname: Gallego-Colon
authors.affiliation: Institute Pasteur Cenci-Bolognetti, DAHFMO-Unit of Histology and Medical Embryology, IIM, Sapienza University of Rome, Rome, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Barberi
authors.affiliation: Mouse Biology Unit, European Molecular Biology Laboratory (EMBL), Monterotondo, Rome, Italy.
authors.forename: Daniel
authors.initials: D
authors.lastname: Bilbao
authors.affiliation: National Heart and Lung Institute, Imperial College London, London, UK.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Schneider
authors.affiliation: Institute Pasteur Cenci-Bolognetti, DAHFMO-Unit of Histology and Medical Embryology, IIM, Sapienza University of Rome, Rome, Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: Musarò
authors.affiliation: Mouse Biology Unit, European Molecular Biology Laboratory (EMBL), Monterotondo, Rome, Italy; National Heart and Lung Institute, Imperial College London, London, UK; Australian Regenerative Medicine Institute/EMBL Australia, Monash University, Melbourne, Australia.
authors.forename: Nadia
authors.initials: N
authors.lastname: Rosenthal
mesh_terms: D000818:Animals; D019898:Autocrine Communication / Q000235:genetics; D018507:Gene Expression Regulation, Developmental; D007249:Inflammation / Q000235:genetics / Q000473:pathology; D007334:Insulin-Like Growth Factor I / Q000096:biosynthesis* / Q000235:genetics; D008264:Macrophages / Q000378:metabolism / Q000473:pathology; D051379:Mice; D009000:Monocytes / Q000378:metabolism; D018482:Muscle, Skeletal / Q000254:growth & development* / Q000378:metabolism; D012038:Regeneration / Q000235:genetics*; D014945:Wound Healing
chemical_list: C519530:insulin-like growth factor-1, mouse; D007334:Insulin-Like Growth Factor I