CCR2 deficiency does not provide sustained improvement of muscular dystrophy in mdx5cv mice

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-1β, IL-6, and IFN-γ genes, a similar level of TNF-α, TGF-β1, and platelet-derived growth factor α genes, and a high level of IGF-1 and osteopontin genes compared to mdx^5cv 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 mdx^5cv mice. Diaphragm MPs from both mdx^5cv-Ccr2^-/- and mdx^5cv 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.-Zhao, W., Wang, X., Ransohoff, R. M., Zhou, L. CCR2 deficiency does not provide sustained improvement of muscular dystrophy in mdx^5cv mice.