Mononuclear phagocytes in muscle after notexin injury in C57Bl/6, Cx3cr1-/-, Ccl2-/-,Cx3cr1-/-Ccl2-/- mice. Mus musculus

Muscle injury triggers inflammation in which infiltrating mononuclear phagocytes are crucial for tissue regeneration. The interaction of the CCL2/CCR2 and CX3CL1/CX3CR1 chemokine axis that guides phagocyte infiltration is incompletely understood. Here, we show that CX3CR1 deficiency promotes muscle repair and rescues Ccl2-/- mice from impaired muscle regeneration as a result of altered macrophage function, not infiltration. Transcriptomic analysis of muscle mononuclear phagocytes reveals that Apolipoprotein E (ApoE) is up-regulated in mice with efficient regeneration. ApoE treatment enhances phagocytosis by mononuclear phagocytes in vitro, and restores phagocytic activity and muscle regeneration in Ccl2-/- mice. Because CX3CR1 deficiency may compensate for defective CCL2-dependant monocyte recruitment by modulating ApoE-dependent macrophage phagocytic activity, targeting CX3CR1 expressed by macrophages might be a powerful therapeutic approach to improve muscle regeneration. Overall design: Mgl1lo, Mgl1Hi, Ly 6c Hi and F4/80 lo mononuclear phagocyte subsets were isolated from muscles 4 days post Notexin injection; Mgl1lo and Mgl1Hi mononuclear phagocyte subsets were isolated from untreated muscles of 4 mice strains: C57Bl/6 (WT), Cx3cr1-/-, Ccl2-/-,Cx3cr1-/-Ccl2-/- (pool of 3 mice per strain and per condition).