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

• 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
• Journal Title: EMBO Molecular Medicine
• Volume: Volume 6, Number 11
• Publisher: Wiley Open Access | 2014-11-01, Pages 1476-1492
• Type of Work: Article | Final Publisher PDF
• Publisher DOI: http://doi.org/10.15252/emmm.201403967
• Subjects: Health Sciences, Pharmacology; Health Sciences, Oncology; Health Sciences, Immunology
• Keywords: Science & Technology; Life Sciences & Biomedicine; Medicine, Research & Experimental; Research & Experimental Medicine; CCR2; chemokines; inflammatory monocytes; macrophage polarization; muscular dystrophy; SKELETAL-MUSCLE INJURY; MDX MICE; MACROPHAGE ACTIVATION; TGF-BETA; ALTERED INFLAMMATION; LOCAL PROLIFERATION; BONE-MARROW; RECRUITMENT; DEFICIENT; POLARIZATION

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.