Journal
JOURNAL OF CELL BIOLOGY
Volume 213, Issue 2, Pages 275-288Publisher
ROCKEFELLER UNIV PRESS
DOI: 10.1083/jcb.201510086
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Funding
- National Institute of Arthritis and Musculoskeletal and Skin Diseases [U54AR052646]
- P30 Muscular Dystrophy Core Center [NIAMS-P30AR057230-01]
- National Institutes of Health [RO1 AR046911, P30 CA016042, 5P30 AI028697]
- Parent Project Muscular Dystrophy
- Muscular Dystrophy Association
- [P30 AR057230]
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In the degenerative disease Duchenne muscular dystrophy, inflammatory cells enter muscles in response to repetitive muscle damage. Immune factors are required for muscle regeneration, but chronic inflammation creates a profibrotic milieu that exacerbates disease progression. Osteopontin (OPN) is an immunomodulator highly expressed in dystrophic muscles. Ablation of OPN correlates with reduced fibrosis and improved muscle strength as well as reduced natural killer T (NKT) cell counts. Here, we demonstrate that the improved dystrophic phenotype observed with OPN ablation does not result from reductions in NKT cells. OPN ablation skews macrophage polarization toward a pro-regenerative phenotype by reducing M1 and M2a and increasing M2c subsets. These changes are associated with increased expression of pro-regenerative factors insulin-like growth factor 1, leukemia inhibitory factor, and urokinase-type plasminogen activator. Furthermore, altered macrophage polarization correlated with increases in muscle weight and muscle fiber diameter, resulting in long-term improvements in muscle strength and function in mdx mice. These findings suggest that OPN ablation promotes muscle repair via macrophage secretion of pro-myogenic growth factors.
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