Expansion and pathogenic activation of skeletal muscle-resident macrophages in mice.

Infiltrating macrophages contribute to muscle dystrophic changes in Duchenne muscular dystrophy (DMD). In a DMD mouse model, mice, CC chemokine receptor type 2 (CCR2) deficiency diminishes Ly6C macrophage infiltration by blocking blood Ly6C inflammatory monocyte recruitment. This is accompanied by transient improvement of muscle damage, fibrosis, and regeneration. The benefit, however, is lost after the expansion of intramuscular Ly6C macrophages. To address the mechanisms underlying the Ly6C macrophage expansion, we compared and mice with and mice, respectively, and found no evidence to suggest Ly6C monocyte recruitment by dystrophic muscles. Single-cell RNA sequencing analysis and -based lineage tracing of macrophage origins demonstrated the expansion and pathogenic activation of muscle resident macrophages in CCR2-deficient mice. The expansion was associated with increased cell proliferation, which appeared induced by colony-stimulating factor-1 (CSF-1) derived from fibro/adipogenic progenitors (FAPs). Our study establishes a pathogenic role for skeletal muscle resident macrophages and supports a regulatory role of FAPs in stimulating the expansion of resident macrophages in the DMD mouse model when the inflammatory macrophage infiltration is inhibited.