title: Mechanosensing by the α6-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 α6-integrin as a mechanosensing integrin subunit that mediates matrix stiffness-regulated myofibroblast invasion. Increasing α6-expression, specifically the B isoform (α6B), couples β1-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 α6-integrin in vitro and in vivo. Genetic ablation of α6 in collagen-expressing mesenchymal cells or pharmacological blockade of matrix stiffness-regulated α6-expression protects mice against bleomycin injury-induced experimental lung fibrosis. These findings suggest that α6-integrin is a matrix stiffness-regulated mechanosensitive molecule which confers an invasive fibroblast phenotype and mediates experimental lung fibrosis. Targeting this mechanosensing α6(β1)-integrin offers a novel anti-fibrotic strategy against lung fibrosis.
authors.affiliation: Department of Medicine, Division of Pulmonary, Allergy and Critical Care Medicine, University of Alabama at Birmingham, Birmingham, Alabama 35294 USA.
authors.forename: Huaping
authors.initials: H
authors.lastname: Chen
authors.affiliation: Department of Medicine, Division of Pulmonary, Allergy and Critical Care Medicine, University of Alabama at Birmingham, Birmingham, Alabama 35294 USA.
authors.forename: Jing
authors.initials: J
authors.lastname: Qu
authors.affiliation: Department of Medicine, Division of Pulmonary, Allergy and Critical Care Medicine, University of Alabama at Birmingham, Birmingham, Alabama 35294 USA.
authors.forename: Xiangwei
authors.initials: X
authors.lastname: Huang
authors.affiliation: Department of Medicine, Division of Pulmonary, Allergy and Critical Care Medicine, University of Alabama at Birmingham, Birmingham, Alabama 35294 USA.
authors.forename: Ashish
authors.initials: A
authors.lastname: Kurundkar
authors.affiliation: The Second Xiangya Hospital, Central-South University, Changsha 410011, China.
authors.forename: Lanyan
authors.initials: L
authors.lastname: Zhu
authors.affiliation: Department of Medicine, Division of Pulmonary, Allergy and Critical Care Medicine, University of Alabama at Birmingham, Birmingham, Alabama 35294 USA.
authors.forename: Naiheng
authors.initials: N
authors.lastname: Yang
authors.affiliation: Department of Medicine, Division of Pulmonary, Allergy and Critical Care Medicine, University of Alabama at Birmingham, Birmingham, Alabama 35294 USA.|Department of Medicine, University of California at San Francisco, San Francisco, California 94143 USA.
authors.forename: Aida
authors.initials: A
authors.lastname: Venado
authors.affiliation: Department of Medicine, Division of Pulmonary, Allergy and Critical Care Medicine, University of Alabama at Birmingham, Birmingham, Alabama 35294 USA.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Ding
authors.affiliation: Department of Medicine, Division of Pulmonary, Allergy and Critical Care Medicine, University of Alabama at Birmingham, Birmingham, Alabama 35294 USA.
authors.forename: Gang
authors.initials: G
authors.lastname: Liu
authors.affiliation: Department of Medicine, Division of Pulmonary, Allergy and Critical Care Medicine, University of Alabama at Birmingham, Birmingham, Alabama 35294 USA.
authors.forename: Veena B
authors.initials: VB
authors.lastname: Antony
authors.affiliation: Department of Medicine, Division of Pulmonary, Allergy and Critical Care Medicine, University of Alabama at Birmingham, Birmingham, Alabama 35294 USA.
authors.forename: Victor J
authors.initials: VJ
authors.lastname: Thannickal
authors.affiliation: Department of Medicine, Division of Pulmonary, Allergy and Critical Care Medicine, University of Alabama at Birmingham, Birmingham, Alabama 35294 USA.
authors.forename: Yong
authors.initials: Y
authors.lastname: Zhou
mesh_terms: D000818:Animals; D001485:Basement Membrane / Q000378:metabolism / Q000473:pathology; D001761:Bleomycin; D002448:Cell Adhesion; D005109:Extracellular Matrix / Q000378:metabolism; D005347:Fibroblasts / Q000473:pathology*; D017353:Gene Deletion; D006801:Humans; D039503:Integrin alpha6 / Q000378:metabolism*; D008168:Lung / Q000378:metabolism* / Q000473:pathology*; D040542:Mechanotransduction, Cellular / Q000235:genetics; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D058628:Myofibroblasts / Q000378:metabolism / Q000473:pathology; D010641:Phenotype; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D011658:Pulmonary Fibrosis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D015854:Up-Regulation; D054460:rho-Associated Kinases / Q000378:metabolism
chemical_list: D039503:Integrin alpha6; D016760:Proto-Oncogene Proteins c-fos; D001761:Bleomycin; D054460:rho-Associated Kinases