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

• Type of Material: Article
• Authors: Kamalika Mojumdar, McGill University; Feng Liang, McGill University; Christian Giordano, McGill University; Christian Lemaire, McGill University; Gawiyou Danialou, McGill University; Tatsuma Okazaki, McGill University; Johanne Bourdon, McGill University; Moutih Rafei, University of Montreal; Jacques Galipeau, Emory University; Maziar Divangahi, McGill University; Basil J. Petrof, McGill University
• Language: English
• Date: 2014-11-01
• Publisher: Wiley Open Access
• Publication Version: Final Published Version
• Copyright Statement: © 2014 The Authors.
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.15252/emmm.201403967
• Title of Journal or Parent Work: EMBO Molecular Medicine
• ISSN: 1757-4676
• Volume: 6
• Issue: 11
• Start Page: 1476
• End Page: 1492
• Grant/Funding Information: This investigation was supported by the Canadian Institutes of Health Research, the Fonds de la Recherche en Santé du Québec, and the McGill University Health Centre Research Institute.
• Keywords: RECRUITMENT; chemokines; POLARIZATION; BONE-MARROW; DEFICIENT; TGF-BETA; inflammatory monocytes; MACROPHAGE ACTIVATION; ALTERED INFLAMMATION; MDX MICE; macrophage polarization; CCR2; muscular dystrophy; Medicine, Research & Experimental; SKELETAL-MUSCLE INJURY; LOCAL PROLIFERATION; Science & Technology; Life Sciences & Biomedicine; Research & Experimental Medicine
• Research Categories: Health Sciences, Immunology; Health Sciences, Oncology; Health Sciences, Pharmacology

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 (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.