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 Ly6Cpos macrophages exhibit a profibrotic activity by sustaining fibroblast production of collagen I. This is mediated by the high production of latent-TGF-β1 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 Ly6Cpos macrophages, blunts the production of latent-TGF-β1, and eventually reduces fibrosis and improves DMD muscle force. Moreover, fibro-adipogenic progenitors are the main providers of TGF-β-activating enzymes in mouse and human DMD, leading to collagen production by fibroblasts. In vivo pharmacological inhibition of TGF-β-activating enzymes improves the dystrophic phenotype. Thus, an AMPK-LTBP4 axis in inflammatory macrophages controls the production of TGF-β1, which is further activated by and acts on fibroblastic cells, leading to fibrosis in DMD. Juban et al. show that, in DMD muscle, macrophages produce LTBP4, inducing the secretion of latent TGF-β1. Fibroblast-derived enzymes activate TGF-β1, which promotes collagen secretion by fibroblasts. AMPK activation inhibits LTBP4 expression and TGF-β1 production by macrophages. Metformin treatment of DMD mice reduces fibrosis and increases muscle regeneration and strength.

AMPK Activation Regulates LTBP4-Dependent TGF-β1 Secretion by Pro-inflammatory Macrophages and Controls Fibrosis in Duchenne Muscular Dystrophy / G. Juban, M. Saclier, H. Yacoub-Youssef, A. Kernou, L. Arnold, C. Boisson, S. Ben Larbi, M. Magnan, S. Cuvellier, M. Theret, B.J. Petrof, I. Desguerre, J. Gondin, R. Mounier, B. Chazaud. - In: CELL REPORTS. - ISSN 2211-1247. - 25:8(2018 Nov), pp. 2163-2176.

AMPK Activation Regulates LTBP4-Dependent TGF-β1 Secretion by Pro-inflammatory Macrophages and Controls Fibrosis in Duchenne Muscular Dystrophy

Saclier M.;
2018-11

Abstract

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 Ly6Cpos macrophages exhibit a profibrotic activity by sustaining fibroblast production of collagen I. This is mediated by the high production of latent-TGF-β1 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 Ly6Cpos macrophages, blunts the production of latent-TGF-β1, and eventually reduces fibrosis and improves DMD muscle force. Moreover, fibro-adipogenic progenitors are the main providers of TGF-β-activating enzymes in mouse and human DMD, leading to collagen production by fibroblasts. In vivo pharmacological inhibition of TGF-β-activating enzymes improves the dystrophic phenotype. Thus, an AMPK-LTBP4 axis in inflammatory macrophages controls the production of TGF-β1, which is further activated by and acts on fibroblastic cells, leading to fibrosis in DMD. Juban et al. show that, in DMD muscle, macrophages produce LTBP4, inducing the secretion of latent TGF-β1. Fibroblast-derived enzymes activate TGF-β1, which promotes collagen secretion by fibroblasts. AMPK activation inhibits LTBP4 expression and TGF-β1 production by macrophages. Metformin treatment of DMD mice reduces fibrosis and increases muscle regeneration and strength.
AMP-Activated Protein Kinases; Animals; Biomarkers; Disease Models, Animal; Enzyme Activation; Fibroblasts; Fibrosis; Inflammation; Latent TGF-beta Binding Proteins; Macrophages; Mice; Mice, Inbred C57BL; Muscle, Skeletal; Muscular Dystrophy, Duchenne; NIH 3T3 Cells; Transforming Growth Factor beta1
Settore BIO/17 - Istologia
CELL REPORTS
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/2434/735661
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