Inflammatory monocytes promote progression of Duchenne muscular dystrophy and can be therapeutically targeted via CCR2Reportar como inadecuado

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Journal Title:

EMBO Molecular Medicine


Volume 6, Number 11


Wiley Open Access | 2014-11-01, Pages 1476-1492

Type of Work:

Article | Final Publisher PDF

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.

Subjects: Health Sciences, Pharmacology - Health Sciences, Oncology - Health Sciences, Immunology - Research Funding: 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: Science and Technology - Life Sciences and Biomedicine - Medicine, Research and Experimental - Research and 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 -

Autor: Kamalika Mojumdar, Feng Liang, Christian Giordano, Christian Lemaire, Gawiyou Danialou, Tatsuma Okazaki, Johanne Bourdon, Moutih



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