title: Fibrinogen drives dystrophic muscle fibrosis via a TGFbeta/alternative macrophage activation pathway.
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-1beta, drives the synthesis of transforming growth factor-beta (TGFbeta) by mdx macrophages, which in turn induces collagen production in mdx fibroblasts. Fibrinogen-produced TGFbeta further amplifies collagen accumulation through activation of profibrotic alternatively activated macrophages. Fibrinogen, by engaging its alphavbeta3 receptor on fibroblasts, also directly promotes collagen synthesis. These data unveil a profibrotic role of fibrinogen deposition in muscle dystrophy.
authors.affiliation: Program on Differentiation and Cancer, Center for Genomic Regulation (CRG), Pompeu Fabra University (UPF), E-08003 Barcelona, Spain.
authors.forename: Berta
authors.initials: B
authors.lastname: Vidal
authors.forename: Antonio L
authors.initials: AL
authors.lastname: Serrano
authors.forename: Marc
authors.initials: M
authors.lastname: Tjwa
authors.forename: Mònica
authors.initials: M
authors.lastname: Suelves
authors.forename: Esther
authors.initials: E
authors.lastname: Ardite
authors.forename: Roberta
authors.initials: R
authors.lastname: De Mori
authors.forename: Bernat
authors.initials: B
authors.lastname: Baeza-Raja
authors.forename: María
authors.initials: M
authors.lastname: Martínez de Lagrán
authors.forename: Peggy
authors.initials: P
authors.lastname: Lafuste
authors.forename: Vanessa
authors.initials: V
authors.lastname: Ruiz-Bonilla
authors.forename: Mercè
authors.initials: M
authors.lastname: Jardí
authors.forename: Romain
authors.initials: R
authors.lastname: Gherardi
authors.forename: Christo
authors.initials: C
authors.lastname: Christov
authors.forename: Mara
authors.initials: M
authors.lastname: Dierssen
authors.forename: Peter
authors.initials: P
authors.lastname: Carmeliet
authors.forename: Jay L
authors.initials: JL
authors.lastname: Degen
authors.forename: Mieke
authors.initials: M
authors.lastname: Dewerchin
authors.forename: Pura
authors.initials: P
authors.lastname: Muñoz-Cánoves
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D002648:Child; D002675:Child, Preschool; D003094:Collagen / Q000378:metabolism; D005340:Fibrinogen / Q000502:physiology*; D005347:Fibroblasts / Q000378:metabolism; D005355:Fibrosis; D006801:Humans; D039302:Integrin alphaVbeta3 / Q000378:metabolism; D053583:Interleukin-1beta / Q000378:metabolism; D008262:Macrophage Activation / Q000502:physiology*; D016177:Macrophage-1 Antigen / Q000378:metabolism; D008264:Macrophages / Q000502:physiology; D051379:Mice; D018101:Mice, Inbred mdx; D018482:Muscle, Skeletal / Q000378:metabolism / Q000473:pathology; D009137:Muscular Dystrophy, Animal / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D020388:Muscular Dystrophy, Duchenne / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D011485:Protein Binding; D016212:Transforming Growth Factor beta / Q000378:metabolism*
chemical_list: D039302:Integrin alphaVbeta3; D053583:Interleukin-1beta; D016177:Macrophage-1 Antigen; D016212:Transforming Growth Factor beta; D005340:Fibrinogen; D003094:Collagen