Fibrinogen drives dystrophic muscle fibrosis via a TGFbeta/alternative macrophage activation pathway
Vidal, Berta × Serrano, Antonio L Tjwa, Marc Suelves, Mònica Ardite, Esther De Mori, Roberta Baeza-Raja, Bernat Martínez de Lagrán, María Lafuste, Peggy Ruiz-Bonilla, Vanessa Jardí, Mercè Gherardi, Romain Christov, Christo Dierssen, Mara Carmeliet, Peter Degen, Jay L Dewerchin, Mieke Muñoz-Cánoves, Pura #
Cold spring harbor lab press, publications dept
Genes & development vol:22 issue:13 pages:1747-52
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.