Inflammatory monocytes promote progression of Duchenne muscular dystrophy and can be therapeutically targeted via CCR2

Kamalika Mojumdar, Feng Liang, Christian Giordano, Christian Lemaire, Gawiyou Danialou, Tatsuma Okazaki, Johanne Bourdon, Moutih Rafei, Jacques Galipeau, Maziar Divangahi, Basil J. Petrof

研究成果: Article査読

76 被引用数 (Scopus)

抄録

Myofiber necrosis and fibrosis are hallmarks of Duchenne muscular dystrophy (DMD), leading to lethal weakness of the diaphragm. Macrophages (MPs) are required for successful muscle regeneration, but the role of inflammatory monocyte (MO)-derived MPs in either promoting or mitigating DMD is unclear. We show that DMD (mdx) mouse diaphragms exhibit greatly increased expression of CCR2 and its chemokine ligands, along with inflammatory (Ly6Chigh) MO recruitment and accumulation of CD11bhigh MO-derived MPs. Loss-of-function of CCR2 preferentially reduced this CD11bhigh MP population by impeding the release of Ly6Chigh MOs from the bone marrow but not the splenic reservoir. CCR2 deficiency also helped restore the MP polarization balance by preventing excessive skewing of MPs toward a proinflammatory phenotype. These effects were linked to amelioration of histopathological features and increased muscle strength in the diaphragm. Chronic inhibition of CCR2 signaling by mutated CCL2 secreted from implanted mesenchymal stem cells resulted in similar improvements. These data uncover a previously unrecognized role of inflammatory MOs in DMD pathogenesis and indicate that CCR2 inhibition could offer a novel strategy for DMD management. Synopsis: Inflammatory macrophages are shown here to play a central role in the mdx-mouse pathology, a model for Duchenne muscular dystrophy. Genetic ablation or pharmacologic inhibition of CCR2 confers therapeutic benefits in animals, improving muscle structure and function. CD11b(high) macrophages (MP) derived from Ly6C(high) inflammatory monocytes are key pathogenesis mediators in the mdx mouse model of Duchenne muscular dystrophy. Loss of CCR2 preferentially reduces CD11b(high) MP accumulation in the mdx diaphragm and mitigates proinflammatory polarization of intramuscular MP. Genetic as well as pharmacological blockade of CCR2 in mdx mice ameliorates dystrophic histopathologic features and improves mdx diaphragm muscle force production. CCR2 blockade may serve as a useful therapeutic modulator of the immune response in muscular dystrophy. Inflammatory macrophages are shown here to play a central role in the mdx-mouse pathology, a model for Duchenne muscular dystrophy. Genetic ablation or pharmacologic inhibition of CCR2 confers therapeutic benefits in animals, improving muscle structure and function.

本文言語English
ページ(範囲)1476-1492
ページ数17
ジャーナルEMBO Molecular Medicine
6
11
DOI
出版ステータスPublished - 2014 11月 1
外部発表はい

ASJC Scopus subject areas

  • 分子医療

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