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.