Mechanosensing by the α(6)-integrin confers an invasive fibroblast phenotype and mediates lung fibrosis

Matrix stiffening is a prominent feature of pulmonary fibrosis. In this study, we demonstrate that matrix stiffness regulates the ability of fibrotic lung myofibroblasts to invade the basement membrane (BM). We identify α(6)-integrin as a mechanosensing integrin subunit that mediates matrix stiffness-regulated myofibroblast invasion. Increasing α(6)-expression, specifically the B isoform (α(6)B), couples β(1)-integrin to mediate MMP-2-dependent pericellular proteolysis of BM collagen IV, leading to myofibroblast invasion. Human idiopathic pulmonary fibrosis lung myofibroblasts express high levels of α(6)-integrin in vitro and in vivo. Genetic ablation of α(6) in collagen-expressing mesenchymal cells or pharmacological blockade of matrix stiffness-regulated α(6)-expression protects mice against bleomycin injury-induced experimental lung fibrosis. These findings suggest that α(6)-integrin is a matrix stiffness-regulated mechanosensitive molecule which confers an invasive fibroblast phenotype and mediates experimental lung fibrosis. Targeting this mechanosensing α(6)(β(1))-integrin offers a novel anti-fibrotic strategy against lung fibrosis.