Journal
FASEB JOURNAL
Volume 31, Issue 1, Pages 35-46Publisher
FEDERATION AMER SOC EXP BIOL
DOI: 10.1096/fj.201600619R
Keywords
fibrosis; inflammation; macrophages; regeneration
Categories
Funding
- U.S. National Institutes of Health, National Institute of Arthritis and Musculoskeletal and Skin Diseases [R01AR059702]
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Genetic ablation or pharmacologic inhibition of CC chemokine receptor type 2 (CCR2) reduced macrophage (MP) infiltration and improved muscle pathology and function in mdx diaphragm muscle at early stages. We addressed whether CCR2 deficiency resulted in sustained improvement of mdx(5cv)-Ccr2(-/-) diaphragm. Compared to mdx(5cv) controls, CCR2 deficiency in mdx(5cv)-Ccr2(-/-) mice markedly reduced intramuscular Ly6C(hi) MPs at all stages, but it reduced Ly6C(low) MPs only at early stages (4 and 9 wk). CCR2 deficiency reduced quadriceps and diaphragm muscle damage and fibrosis at 14 wk but not at 6 mo, and it improved diaphragm muscle regeneration and respiratory function at 14 wk but not at 6 mo. Intramuscular MPs in mdx(5cv)-Ccr2(-/-) diaphragm expressed a low level of IL-1 beta, IL-6, and IFN-gamma genes, a similar level of TNF-alpha, TGF-beta 1, and platelet-derived growth factor a genes, and a high level of IGF-1 and osteopontin genes compared to mdx5cv controls. Diaphragm fibroblasts at 14 wk showed a similar cell number with a similar level of collagen and profibrogenic growth factor gene expression in mdx(5cv)-Ccr2(-/-) and mdx5cv mice. Diaphragm MPs from both mdx(5cv)-Ccr2(-/-) and mdx5cv mice stimulated collagen gene expression by cocultured fibroblasts. The findings suggest that CCR2 deficiency does not provide a sustained benefit and that Ly6C(low) MPs may contribute to the progressive fibrosis and dysfunction of mdx(5cv) diaphragm.
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