Selective ablation of Nfix in macrophages attenuates muscular dystrophy by inhibiting fibro‐adipogenic progenitor‐dependent fibrosis

• Published in: The Journal of pathology Vol. 257; no. 3; pp. 352 - 366
• Main Authors: Saclier, Marielle, Angelini, Giuseppe, Bonfanti, Chiara, Mura, Giada, Temponi, Giulia, Messina, Graziella
• Format: Journal Article
• Language: English
• Published: Chichester, UK John Wiley & Sons, Ltd 01.07.2022; Wiley Subscription Services, Inc; Wiley
• Subjects: Animal models; Animals; Apoptosis; Drug therapy; Fibrosis; fibro‐adipogenic progenitors; Genetic disorders; inflammation; Inflammation - pathology; Life Sciences; macrophage; Macrophages; Macrophages - pathology; Mice; Mice, Inbred mdx; Muscle, Skeletal - pathology; Muscular Dystrophies - metabolism; Muscular Dystrophies - pathology; Muscular dystrophy; NFI Transcription Factors - genetics; Nfix; Original; Progenitor cells; Transforming growth factor-b1; Tumor necrosis factor-α; United Kingdom; United Kingdom; macrophage; Nfix; muscular dystrophy; fibrosis; inflammation; fibro-adipogenic progenitors
• ISSN: 0022-3417; 1096-9896
• DOI: 10.1002/path.5895

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.