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Mol Ther. 2015 Jul;23(7):1189-1200. doi: 10.1038/mt.2015.66. Epub 2015 Apr 21.

Monocyte/Macrophage-derived IGF-1 Orchestrates Murine Skeletal Muscle Regeneration and Modulates Autocrine Polarization.

Author information

1
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.
2
Mouse Biology Unit, European Molecular Biology Laboratory (EMBL), Monterotondo, Rome, Italy; Current address: Department of Pathology, Maastricht University (CARIM), Maastricht, The Netherlands.
3
National Heart and Lung Institute, Imperial College London, London, UK.
4
Institute Pasteur Cenci-Bolognetti, DAHFMO-Unit of Histology and Medical Embryology, IIM, Sapienza University of Rome, Rome, Italy.
5
Mouse Biology Unit, European Molecular Biology Laboratory (EMBL), Monterotondo, Rome, Italy.
6
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.

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.

PMID:
25896247
PMCID:
PMC4817788
DOI:
10.1038/mt.2015.66
[Indexed for MEDLINE]
Free PMC Article
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