Mechanosensing by the ?6-integrin confers an invasive fibroblast phenotype and mediates lung fibrosis.

ABSTRACT: 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 ?6-integrin as a mechanosensing integrin subunit that mediates matrix stiffness-regulated myofibroblast invasion. Increasing ?6-expression, specifically the B isoform (?6B), couples ?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 ?6-integrin in vitro and in vivo. Genetic ablation of ?6 in collagen-expressing mesenchymal cells or pharmacological blockade of matrix stiffness-regulated ?6-expression protects mice against bleomycin injury-induced experimental lung fibrosis. These findings suggest that ?6-integrin is a matrix stiffness-regulated mechanosensitive molecule which confers an invasive fibroblast phenotype and mediates experimental lung fibrosis. Targeting this mechanosensing ?6(?1)-integrin offers a novel anti-fibrotic strategy against lung fibrosis.

SUBMITTER: Chen H 

PROVIDER: S-EPMC4992155 | biostudies-literature | 2016 Aug

REPOSITORIES: biostudies-literature