title: Inflammatory monocytes promote progression of Duchenne muscular dystrophy and can be therapeutically targeted via CCR2.
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 (Ly6C(high)) MO recruitment and accumulation of CD11b(high) MO-derived MPs. Loss-of-function of CCR2 preferentially reduced this CD11b(high) MP population by impeding the release of Ly6C(high) 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.
authors.affiliation: Meakins-Christie Laboratories and Respiratory Division, McGill University Health Centre and Research Institute, Montreal, QC, Canada.
authors.forename: Kamalika
authors.initials: K
authors.lastname: Mojumdar
authors.affiliation: Meakins-Christie Laboratories and Respiratory Division, McGill University Health Centre and Research Institute, Montreal, QC, Canada.
authors.forename: Feng
authors.initials: F
authors.lastname: Liang
authors.affiliation: Meakins-Christie Laboratories and Respiratory Division, McGill University Health Centre and Research Institute, Montreal, QC, Canada.
authors.forename: Christian
authors.initials: C
authors.lastname: Giordano
authors.affiliation: Meakins-Christie Laboratories and Respiratory Division, McGill University Health Centre and Research Institute, Montreal, QC, Canada.
authors.forename: Christian
authors.initials: C
authors.lastname: Lemaire
authors.affiliation: Meakins-Christie Laboratories and Respiratory Division, McGill University Health Centre and Research Institute, Montreal, QC, Canada.
authors.forename: Gawiyou
authors.initials: G
authors.lastname: Danialou
authors.affiliation: Meakins-Christie Laboratories and Respiratory Division, McGill University Health Centre and Research Institute, Montreal, QC, Canada.
authors.forename: Tatsuma
authors.initials: T
authors.lastname: Okazaki
authors.affiliation: Meakins-Christie Laboratories and Respiratory Division, McGill University Health Centre and Research Institute, Montreal, QC, Canada.
authors.forename: Johanne
authors.initials: J
authors.lastname: Bourdon
authors.affiliation: Department of Pharmacology, Faculty of Medicine, University of Montreal, Montreal, QC, Canada.
authors.forename: Moutih
authors.initials: M
authors.lastname: Rafei
authors.affiliation: Department of Hematology and Oncology, Winship Cancer Institute, Emory University, Atlanta, GA, USA Department of Pediatrics, Emory University, Atlanta, GA, USA.
authors.forename: Jacques
authors.initials: J
authors.lastname: Galipeau
authors.affiliation: Meakins-Christie Laboratories and Respiratory Division, McGill University Health Centre and Research Institute, Montreal, QC, Canada.
authors.forename: Maziar
authors.initials: M
authors.lastname: Divangahi
authors.affiliation: Meakins-Christie Laboratories and Respiratory Division, McGill University Health Centre and Research Institute, Montreal, QC, Canada basil.petrof@mcgill.ca.
authors.forename: Basil J
authors.initials: BJ
authors.lastname: Petrof
mesh_terms: D000818:Animals; D000950:Antigens, Ly / Q000032:analysis; D039481:CD11b Antigen / Q000032:analysis; D018932:Chemokine CCL2 / Q000378:metabolism*; D003964:Diaphragm / Q000473:pathology; D005260:Female; D007167:Immunotherapy / Q000379:methods*; D008297:Male; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000378:metabolism; D008810:Mice, Inbred C57BL; D018101:Mice, Inbred mdx; D009000:Monocytes / Q000737:chemistry / Q000276:immunology*; D020388:Muscular Dystrophy, Duchenne / Q000276:immunology* / Q000473:pathology / Q000503:physiopathology* / Q000628:therapy; D050505:Mutant Proteins / Q000378:metabolism; D054390:Receptors, CCR2 / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D016896:Treatment Outcome
chemical_list: D000950:Antigens, Ly; D039481:CD11b Antigen; C491768:Ccl2 protein, mouse; C515335:Ccr2 protein, mouse; D018932:Chemokine CCL2; C494192:Ly-6C antigen, mouse; D050505:Mutant Proteins; D054390:Receptors, CCR2
keywords: CCR2; chemokines; inflammatory monocytes; macrophage polarization; muscular dystrophy