Genetic ablation or pharmacologic inhibition of CC chemokine receptor type 2 (CCR2) reduced macrophage (MP) infiltration and improvedmuscle pathology and function in mdx diaphragmmuscle at early stages. We addressed whether CCR2 deficiency resulted in sustained improvement of mdx5cv-Ccr2-/- diaphragm. Compared to mdx5cv controls, CCR2 deficiency in mdx5cv-Ccr2-/- mice markedly reduced intramuscular Ly6Chi MPs at all stages, but it reduced Ly6Clow 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 14wk but not at 6mo. Intramuscular MPs in mdx5cv-Ccr2-/- diaphragmexpressed 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 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 mdx5cv-Ccr2-/- and mdx5cv mice. Diaphragm MPs from both mdx5cv-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 Ly6ClowMPs may contribute to the progressive fibrosis and dysfunction of mdx5cv diaphragm. - Zhao, W., Wang, X., Ransohoff, R. M., Zhou, L. CCR2 deficiency does not provide sustained improvement of muscular dystrophy in mdx5cv.
ASJC Scopus subject areas
- Molecular Biology