Mechanosensing by the α6-integrin confers an invasive fibroblast phenotype and mediates lung fibrosis

Huaping Chen, Jing Qu, Xiangwei Huang, Ashish Kurundkar, Lanyan Zhu, Naiheng Yang, Aida Venado, Qiang Ding, Gang Liu, Veena B. Antony, Victor J. Thannickal and Yong Zhou ()
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Huaping Chen: Allergy and Critical Care Medicine, University of Alabama at Birmingham
Jing Qu: Allergy and Critical Care Medicine, University of Alabama at Birmingham
Xiangwei Huang: Allergy and Critical Care Medicine, University of Alabama at Birmingham
Ashish Kurundkar: Allergy and Critical Care Medicine, University of Alabama at Birmingham
Lanyan Zhu: The Second Xiangya Hospital, Central-South University
Naiheng Yang: Allergy and Critical Care Medicine, University of Alabama at Birmingham
Aida Venado: Allergy and Critical Care Medicine, University of Alabama at Birmingham
Qiang Ding: Allergy and Critical Care Medicine, University of Alabama at Birmingham
Gang Liu: Allergy and Critical Care Medicine, University of Alabama at Birmingham
Veena B. Antony: Allergy and Critical Care Medicine, University of Alabama at Birmingham
Victor J. Thannickal: Allergy and Critical Care Medicine, University of Alabama at Birmingham
Yong Zhou: Allergy and Critical Care Medicine, University of Alabama at Birmingham

Nature Communications, 2016, vol. 7, issue 1, 1-12

Abstract: 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.

Date: 2016
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DOI: 10.1038/ncomms12564

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