title: CCR2 deficiency does not provide sustained improvement of muscular dystrophy in mdx5cv mice.
abstract: 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 mdx5cv-Ccr2-/-diaphragm. Compared to mdx5cvcontrols, CCR2 deficiency in mdx5cv-Ccr2-/-mice markedly reduced intramuscular Ly6ChiMPs at all stages, but it reduced Ly6ClowMPs 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 mdx5cv-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 mdx5cvcontrols. 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 mdx5cvmice. Diaphragm MPs from both mdx5cv-Ccr2-/-and mdx5cvmice 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 mdx5cvdiaphragm.-Zhao, W., Wang, X., Ransohoff, R. M., Zhou, L. CCR2 deficiency does not provide sustained improvement of muscular dystrophy in mdx5cvmice.
authors.affiliation: Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, New York, USA; and.
authors.forename: Wanming
authors.initials: W
authors.lastname: Zhao
authors.affiliation: Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, New York, USA; and.
authors.forename: Xingyu
authors.initials: X
authors.lastname: Wang
authors.affiliation: Neuroimmunology, Biogen, Cambridge, Massachusetts, USA.
authors.forename: Richard M
authors.initials: RM
authors.lastname: Ransohoff
authors.affiliation: Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, New York, USA; and lan.zhou@mssm.edu.
authors.forename: Lan
authors.initials: L
authors.lastname: Zhou
mesh_terms: D000818:Animals; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D003964:Diaphragm; D005355:Fibrosis / Q000378:metabolism / Q000473:pathology; D005786:Gene Expression Regulation / Q000502:physiology*; D051379:Mice; D018101:Mice, Inbred mdx; D018345:Mice, Knockout; D009136:Muscular Dystrophies / Q000235:genetics / Q000378:metabolism*; D054390:Receptors, CCR2 / Q000235:genetics / Q000378:metabolism*
chemical_list: C515335:Ccr2 protein, mouse; D016207:Cytokines; D054390:Receptors, CCR2
keywords: fibrosis; inflammation; macrophages; regeneration