Inflammatory monocytes promote progression of Duchenne muscular dystrophy and can be therapeutically targeted via CCR 2

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.