Journal
CELL REPORTS
Volume 25, Issue 8, Pages 2163-+Publisher
CELL PRESS
DOI: 10.1016/j.celrep.2018.10.077
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Funding
- Framework Programme FP7 Endo-stem [241440]
- Association Francaise contre les Myopathies [16029]
- Fondation pour la Recherche Medicale [Equipe FRM DEQ20140329495]
- Canadian Institutes of Health Research
- Association Francaise contre les Myopathies (MyoNeurAlp Alliance)
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Chronic inflammation and fibrosis characterize Duchenne muscular dystrophy (DMD). We show that pro-inflammatory macrophages are associated with fibrosis in mouse and human DMD muscle. DMD-derived Ly6C(pos) macrophages exhibit a profibrotic activity by sustaining fibroblast production of collagen I. This is mediated by the high production of latent-TGF-beta 1 due to the higher expression of LTBP4, for which polymorphisms are associated with the progression of fibrosis in DMD patients. Skewing macrophage phenotype via AMPK activation decreases ltbp4 expression by Ly6C(pos) macrophages, blunts the production of latent-TGF-beta 1, and eventually reduces fibrosis and improves DMD muscle force. Moreover, fibro-adipogenic progenitors are the main providers of TGF-beta-activating enzymes in mouse and human DMD, leading to collagen production by fibroblasts. In vivo pharmacological inhibition of TGF-beta-activating enzymes improves the dystrophic phenotype. Thus, an AMPK-LTBP4 axis in inflammatory macrophages controls the production of TGF-beta 1, which is further activated by and acts on fibroblastic cells, leading to fibrosis in DMD.
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