Selective ablation of Nfix in Macrophages preserves Muscular Dystrophy by inhibiting FAPs-dependent fibrosis

Abstract

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.

Regenerative inflammation: When immune cells help to re‐build tissues

“…However, the metabolic variations alone cannot explain the magnitude of changes in gene expression observed by bulk RNASeq. Transcriptional regulation through transcription factors such as, C/EBPβ [ 107 ], STAT3 [ 108 ], NFIX [ 109 ], PPARγ [ 84 ] or BACH1 [ 110 ] and epigenetic changes [ 111 – 113 ] have been shown to contribute to the macrophage switch modifying macrophage gene expression, products and function. As a result of transcriptional changes, several signalling pathways involving cytokines [interleukin-6 (IL-6), IL-10], growth factors (IGF1) and lipid mediators (RvD1, RvD2, RvE1) [ 10 , 114 ] enhance further modifications necessary for the macrophage switch.…”