Splenic Ly6Chi monocytes are critical players in dystrophic muscle injury and repair

Dystrophic muscle is characterized by chronic injury and a steady recruitment of inflammatory Ly6C(hi) monocytes. Recent studies have identified the spleen as the dominant reservoir of these cells during chronic inflammation. Here, we investigated the contribution of splenic Ly6C(hi) monocytes to dystrophic muscle pathology. Using the mdx mouse model of muscular dystrophy, we show that Ly6C(hi) monocytes accumulate in great numbers in the spleen over the course of the disease. The chemokine receptor CCR2 was upregulated on Ly6C(hi) monocytes in mdx spleen before disease onset, thereby enabling their recruitment to dystrophic muscle. Splenectomy performed before disease onset significantly reduced the number of Ly6C(hi) monocytes infiltrating dystrophic limb muscle. Moreover, in the absence of splenic Ly6C(hi) monocytes there was a significant reduction in dystrophic muscle inflammation and necrosis, along with improved regeneration during early disease. However, during late disease, a lack of splenic Ly6C(hi) monocytes adversely affected muscle fiber repair, due to a delay in the phenotypic shift of proinflammatory F4/80(+)Ly6C(hi)CD206(lo) to antiinflammatory F4/80(+)Ly6C(lo)CO206(+) macrophages. Overall, we show that the spleen is an indispensable source of Ly6C(hi) monocytes in muscular dystrophy and that splenic monocytes are critical players in both muscle fiber injury and repair.