IRGM1-IRF7 Axis Controls Macrophage Chemotaxis to Orchestrate Skeletal Muscle Regeneration

Efficient skeletal muscle regeneration requires precise orchestration of immune cells. The timely recruitment of macrophages is particularly critical, linking inflammation resolution with repair initiation. However, the intrinsic molecular switches governing this process remain elusive. Here, we identify the Immunity-related GTPase family M1 protein (IRGM1) as a central regulator of macrophage-mediated muscle repair. IRGM1 is dynamically upregulated post-injury, with expression kinetics paralleling macrophage infiltration. Using myeloid-specific knockout mice, we demonstrate that macrophage-derived IRGM1 is essential for skeletal muscle regeneration. Its absence results in persistent inflammation, delayed regeneration, and impaired functional recovery. Mechanistically, IRGM1 cell-autonomously governs the intrinsic chemotactic capacity of macrophages. IRGM1 deficiency disrupts the response to damage signals by impairing the inducible expression of key chemokine receptors, including CCR1, CCR2, and CCR5. We further show that IRGM1 functions by negatively regulating the transcription factor Interferon regulatory factor 7 (IRF7). IRF7 abnormally accumulates in IRGM1-deficient macrophages, suppressing their migratory capacity. Notably, IRF7 knockdown rescues this migratory defect. Our results define a novel IRGM1-IRF7 signaling axis that controls the spatiotemporal dynamics of macrophages during muscle repair. By relieving IRF7-mediated suppression of migration, this axis ensures coordinated skeletal muscle regeneration. Our findings thus provide both a new mechanistic rationale and a potential therapeutic target for regenerative disorders. Macrophage IRGM1 is essential for skeletal muscle regeneration. IRGM1 governs the intrinsic chemotactic capacity of macrophages. A novel IRGM1-IRF7 axis controls macrophage migration during repair. Irf7 knockdown rescues the migratory defect of Irgm1-deficient macrophages.