Fibrinogen drives dystrophic muscle fibrosis via a TGFβ/alternative macrophage activation pathway
- Berta Vidal1,2,9,
- Antonio L. Serrano1,2,9,
- Marc Tjwa3,4,9,
- Mònica Suelves1,
- Esther Ardite1,2,
- Roberta De Mori1,2,
- Bernat Baeza-Raja1,2,
- María Martínez de Lagrán5,6,
- Peggy Lafuste3,
- Vanessa Ruiz-Bonilla1,2,
- Mercè Jardí1,2,
- Romain Gherardi7,
- Christo Christov7,
- Mara Dierssen5,6,
- Peter Carmeliet3,
- Jay L. Degen8,
- Mieke Dewerchin3, and
- Pura Muñoz-Cánoves1,2,10
- 1 Program on Differentiation and Cancer, Center for Genomic Regulation (CRG), Pompeu Fabra University (UPF), E-08003 Barcelona, Spain;
- 2 Biomedicine Research Center on Neurodegenerative Diseases (CIBERNED), E-08003 Barcelona, Spain;
- 3 Center for Transgene Technology and Gene Therapy, Leuven B-3000, Belgium;
- 4 Leibniz AG, Department of Molecular Cardiology, University of Frankfurt, Frankfurt D-60509, Germany;
- 5 Program on Genes and Disease, Center for Genomic Regulation (CRG), Pompeu Fabra University (UPF), E-08003 Barcelona, Spain;
- 6 Biomedicine Research Center on Rare Diseases (CIBERER), E-08003 Barcelona, Spain;
- 7 Institut Mondor de Medecine Moléculaire; INSERM E0011, Créteil F-94010, France;
- 8 Children’s Hospital Research Foundation, Cincinnati, Ohio 45229, USA
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↵9 These authors contributed equally to this work.
Abstract
In the fatal degenerative Duchenne muscular dystrophy (DMD), skeletal muscle is progressively replaced by fibrotic tissue. Here, we show that fibrinogen accumulates in dystrophic muscles of DMD patients and mdx mice. Genetic loss or pharmacological depletion of fibrinogen in these mice reduced fibrosis and dystrophy progression. Our results demonstrate that fibrinogen–Mac-1 receptor binding, through induction of IL-1β, drives the synthesis of transforming growth factor-β (TGFβ) by mdx macrophages, which in turn induces collagen production in mdx fibroblasts. Fibrinogen-produced TGFβ further amplifies collagen accumulation through activation of profibrotic alternatively activated macrophages. Fibrinogen, by engaging its αvβ3 receptor on fibroblasts, also directly promotes collagen synthesis. These data unveil a profibrotic role of fibrinogen deposition in muscle dystrophy.
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Footnotes
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↵10 Corresponding author.
↵10 E-MAIL pura.munoz{at}crg.es; FAX 34-93-3160099.
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Supplemental material is available at http://www.genesdev.org.
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Article is online at http://www.genesdev.org/cgi/doi/10.1101/gad.465908.
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- Received November 30, 2007.
- Accepted April 28, 2008.
- Copyright © 2008, Cold Spring Harbor Laboratory Press
