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

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

  • Cell Rep. 2018 Nov 20;25(8):2163-2176.e6. doi: 10.1016/j.celrep.2018.10.077.
Gaëtan Juban 1,  Marielle Saclier 2,  Houda Yacoub-Youssef 2,  Amel Kernou 2,  Ludovic Arnold 3,  Camille Boisson 1,  Sabrina Ben Larbi 1,  Mélanie Magnan 2,  Sylvain Cuvellier 2,  Marine Théret 1,  Basil J Petrof 4,  Isabelle Desguerre 2,  Julien Gondin 1,  Rémi Mounier 1,  Bénédicte Chazaud 5
Affiliations

Affiliations

  • 1 Institut NeuroMyoGène, Université Claude Bernard Lyon 1, CNRS UMR 5310, INSERM U1217, Université Lyon, Villeurbanne 69100, France.
  • 2 Institut Cochin, INSERM U1016, CNRS UMR 8104, Université Paris Descartes, Sorbonne Paris Cité, Paris 75014, France.
  • 3 Centre d'Immunologie et des Maladies Infectieuses, INSERM U1135, Université Pierre et Marie Curie, Sorbonne Universités, Paris 75013, France.
  • 4 Meakins-Christie Laboratories, McGill University, Montreal, QC H4A3J1, Canada; Research Institute of the McGill University Health Centre, Montreal, QC H4A3J1, Canada.
  • 5 Institut NeuroMyoGène, Université Claude Bernard Lyon 1, CNRS UMR 5310, INSERM U1217, Université Lyon, Villeurbanne 69100, France. Electronic address: benedicte.chazaud@inserm.fr.
PMID: 30463013 DOI: 10.1016/j.celrep.2018.10.077
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.

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