Open AccessInflammatory monocytes promote progression of Duchenne muscular dystrophy and can be therapeutically targeted via CCR 2
Author(s) -
Mojumdar Kamalika,
Liang Feng,
Giordano Christian,
Lemaire Christian,
Danialou Gawiyou,
Okazaki Tatsuma,
Bourdon Johanne,
Rafei Moutih,
Galipeau Jacques,
Divangahi Maziar,
Petrof Basil J
Publication year - 2014
Publication title -
embo molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.923
H-Index - 107
eISSN - 1757-4684
pISSN - 1757-4676
DOI - 10.15252/emmm.201403967
Subject(s) - duchenne muscular dystrophy , proinflammatory cytokine , muscular dystrophy , chemokine , population , regeneration (biology) , pathogenesis , dystrophin , immunology , inflammation , mesenchymal stem cell , medicine , cancer research , microbiology and biotechnology , biology , environmental health
Myofiber necrosis and fibrosis are hallmarks of Duchenne muscular dystrophy ( DMD ), leading to lethal weakness of the diaphragm. Macrophages ( MP s) are required for successful muscle regeneration, but the role of inflammatory monocyte ( MO )‐derived MP s in either promoting or mitigating DMD is unclear. We show that DMD (mdx) mouse diaphragms exhibit greatly increased expression of CCR 2 and its chemokine ligands, along with inflammatory (Ly6C high ) MO recruitment and accumulation of CD 11b high MO ‐derived MP s. Loss‐of‐function of CCR 2 preferentially reduced this CD 11b high MP population by impeding the release of Ly6C high MO s from the bone marrow but not the splenic reservoir. CCR 2 deficiency also helped restore the MP polarization balance by preventing excessive skewing of MP s toward a proinflammatory phenotype. These effects were linked to amelioration of histopathological features and increased muscle strength in the diaphragm. Chronic inhibition of CCR 2 signaling by mutated CCL 2 secreted from implanted mesenchymal stem cells resulted in similar improvements. These data uncover a previously unrecognized role of inflammatory MO s in DMD pathogenesis and indicate that CCR 2 inhibition could offer a novel strategy for DMD management.