Muscular dystrophies are genetic diseases characterized by chronic inflammation and fibrosis. Macrophages are immune cells that sustain muscle regeneration upon acute injury but seem deleterious in the context of chronic muscle injury such as in muscular dystrophies. Here, we observed that the number of macrophages expressing the transcription factor Nfix increases in two distinct mouse models of muscular dystrophies. We showed that the deletion of Nfix in macrophages in dystrophic mice delays the establishment of fibrosis and muscle wasting, and increases grasp force. Macrophages lacking Nfix expressed more TNFα and less TGFβ1, thus promoting apoptosis of fibro‐adipogenic progenitors. Moreover, pharmacological treatment of dystrophic mice with a ROCK inhibitor accelerated fibrosis through the increase of Nfix expression by macrophages. Thus, we have identified Nfix as a macrophage profibrotic factor in muscular dystrophies, whose inhibition could be a therapeutic route to reduce severity of the dystrophic disease. © 2022 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Muscular dystrophies are genetic diseases characterized by chronic inflammation and fibrosis. Macrophages are immune cells that sustain muscle regeneration upon acute injury but seem deleterious in the context of chronic muscle injury such as muscular dystrophies. Here we observed that the number of macrophages expressing the transcription factor Nfix increases in two distinct murine models of muscular dystrophies. Plus, we showed that the deletion of Nfix in macrophages in dystrophic mice delays fibrosis establishment and muscle wasting until 6 months of life. Indeed, macrophages lacking Nfix express more TNFα and less TGFβ1 thus promoting apoptosis of fibro-adipogenic progenitors. Moreover, pharmacological treatment of dystrophic mice with ROCK inhibitor accelerates fibrosis through the increase of Nfix expression by macrophages. Thus, we identify Nfix as a macrophage profibrotic actor in muscular dystrophies, whose inhibition could be a therapeutic way to rescue the dystrophic disease.