Ablation of integrin-mediated cell-collagen communication alleviates fibrosis

ObjectivesActivation of fibroblasts is a hallmark of fibrotic processes. Besides cytokines and growth factors, fibroblasts are regulated by the extracellular matrix environment through receptors such as integrins, which transduce biochemical and mechanical signals enabling cells to mount appropriate responses according to biological demands. The aim of this work was to investigate the in vivo role of collagen-fibroblast interactions for regulating fibroblast functions and fibrosis. MethodsTriple knockout (tKO) mice with a combined ablation of integrins & alpha;1 & beta;1, & alpha;2 & beta;1 and & alpha;11 & beta;1 were created to address the significance of integrin-mediated cell-collagen communication. Properties of primary dermal fibroblasts lacking collagen-binding integrins were delineated in vitro. Response of the tKO mice skin to bleomycin induced fibrotic challenge was assessed. ResultsTriple integrin-deficient mice develop normally, are transiently smaller and reveal mild alterations in mechanoresilience of the skin. Fibroblasts from these mice in culture show defects in cytoskeletal architecture, traction stress generation, matrix production and organisation. Ablation of the three integrins leads to increased levels of discoidin domain receptor 2, an alternative receptor recognising collagens in vivo and in vitro. However, this overexpression fails to compensate adhesion and spreading defects on collagen substrates in vitro. Mice lacking collagen-binding integrins show a severely attenuated fibrotic response with impaired mechanotransduction, reduced collagen production and matrix organisation. ConclusionsThe data provide evidence for a crucial role of collagen-binding integrins in fibroblast force generation and differentiation in vitro and for matrix deposition and tissue remodelling in vivo. Targeting fibroblast-collagen interactions might represent a promising therapeutic approach to regulate connective tissue deposition in fibrotic diseases.

Automated summary

This study investigates the role of collagen-fibroblast interactions in regulating fibroblast functions and fibrosis. The results show that fibroblasts lacking collagen-binding integrins exhibit defects in cytoskeletal architecture, traction stress generation, and matrix production and organization. Mice lacking collagen-binding integrins also display an attenuated fibrotic response with impaired mechanotransduction and reduced collagen production. These findings suggest that targeting fibroblast-collagen interactions could be a promising therapeutic approach for fibrotic diseases.