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

EMBO Molecular Medicine

Kamalika Mojumdar³  Feng Liang³  Christian Giordano³  Christian Lemaire³  Gawiyou Danialou³  Tatsuma Okazaki³  Johanne Bourdon³  Moutih Rafei¹  Jacques Galipeau²  Maziar Divangahi³ 

[1] Department of Pharmacology, Faculty of Medicine, University of Montreal, Montreal, QC, Canada;Department of Hematology and Oncology, Winship Cancer Institute, Emory University, Atlanta, GA, USA;Meakins-Christie Laboratories and Respiratory Division, McGill University Health Centre and Research Institute, Montreal, QC, Canada

关键词: CCR2;    chemokines;    inflammatory monocytes;    macrophage polarization;    muscular dystrophy;   

DOI  :  10.15252/emmm.201403967

来源: Wiley

【 摘 要 】

Abstract

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 (Ly6C^high) MO recruitment and accumulation of CD11b^high MO-derived MPs. Loss-of-function of CCR2 preferentially reduced this CD11b^high MP population by impeding the release of Ly6C^high 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.

【 授权许可】

CC BY   
© 2014 The Authors. Published under the terms of the CC BY 4.0 license

Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.