Fibrinogen drives dystrophic muscle fibrosis via a TGFbeta/alternative macrophage activation pathway.
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.
Vidal
Berta
B
Program on Differentiation and Cancer, Center for Genomic Regulation (CRG), Pompeu Fabra University (UPF), E-08003 Barcelona, Spain.
Serrano
Antonio L
AL
Tjwa
Marc
M
Suelves
Mònica
M
Ardite
Esther
E
De Mori
Roberta
R
Baeza-Raja
Bernat
B
Martínez de Lagrán
María
M
Lafuste
Peggy
P
Ruiz-Bonilla
Vanessa
V
Jardí
Mercè
M
Gherardi
Romain
R
Christov
Christo
C
Dierssen
Mara
M
Carmeliet
Peter
P
Degen
Jay L
JL
Dewerchin
Mieke
M
Muñoz-Cánoves
Pura
P
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*
D039302:Integrin alphaVbeta3; D053583:Interleukin-1beta; D016177:Macrophage-1 Antigen; D016212:Transforming Growth Factor beta; D005340:Fibrinogen; D003094:Collagen