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 TNF alpha and less TGF beta 1, 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.

Selective ablation of Nfix in macrophages attenuates muscular dystrophy by inhibiting fibro‐adipogenic progenitor‐dependent fibrosis / M. Saclier, G. Angelini, C. Bonfanti, G. Mura, G. Temponi, G. Messina. - In: JOURNAL OF PATHOLOGY. - ISSN 0022-3417. - 257:3(2022 Jul), pp. 352-366. [10.1002/path.5895]

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

M. Saclier
Conceptualization
;
G. Angelini
Methodology
;
C. Bonfanti
Methodology
;
G. Mura
Methodology
;
G. Temponi
Methodology
;
G. Messina
Ultimo
Funding Acquisition
2022

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 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 TNF alpha and less TGF beta 1, 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.
fibro-adipogenic progenitors; fibrosis; inflammation; macrophage; muscular dystrophy; Nfix;
Settore BIO/17 - Istologia
   Role of the transcription factor Nfix in muscle regeneration and muscular dystrophies (RegeneratioNfix)
   RegeneratioNfix
   EUROPEAN COMMISSION
   FP7
   280611
lug-2022
13-apr-2022
Article (author)
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2434/916872
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