IFN-γ Promotes Muscle Damage in the mdx Mouse Model of Duchenne Muscular Dystrophy by Suppressing M2 Macrophage Activation and Inhibiting Muscle Cell Proliferation

Duchenne muscular dystrophy is a degenerative disorder that leads to death by the third decade of life. Previous investigations have shown that macrophages that invade dystrophic muscle are a heterogeneous population consisting of M1 and M2 macrophages that promote injury and repair, respectively. In the present investigation, we tested whether IFN-gamma worsens the severity of mdx dystrophy by activating macrophages to a cytolytic M1 phenotype and by suppressing the activation of proregenerative macrophages to an M2 phenotype. IFN-gamma is a strong inducer of the M1 phenotype and is elevated in mdx dystrophy. Contrary to our expectations, null mutation of IFN-gamma caused no reduction of cytotoxicity of macrophages isolated from mdx muscle and did not reduce muscle fiber damage in vivo or improve gross motor function of mdx mice at the early, acute peak of pathology. In contrast, ablation of IFN-gamma reduced muscle damage in vivo during the regenerative stage of the disease and increased activation of the M2 phenotype and improved motor function of mdx mice at that later stage of the disease. IFN-gamma also inhibited muscle cell proliferation and differentiation in vitro, and IFN-gamma mutation increased MyoD expression in mdx muscle in vivo, showing that IFN-gamma can have direct effects on muscle cells that could impair repair. Taken together, the findings show that suppression of IFN-gamma signaling in muscular dystrophy reduces muscle damage and improves motor performance by promoting the M2 macrophage phenotype and by direct actions on muscle cells. The Journal of Immunology, 2011, 187: 5419-5428.