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

Author

Listed:
  • 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
    University of California at San Francisco)

  • 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)

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.

Suggested Citation

  • Huaping Chen & Jing Qu & Xiangwei Huang & Ashish Kurundkar & Lanyan Zhu & Naiheng Yang & Aida Venado & Qiang Ding & Gang Liu & Veena B. Antony & Victor J. Thannickal & Yong Zhou, 2016. "Mechanosensing by the α6-integrin confers an invasive fibroblast phenotype and mediates lung fibrosis," Nature Communications, Nature, vol. 7(1), pages 1-12, November.
    • Handle: RePEc:nat:natcom:v:7:y:2016:i:1:d:10.1038_ncomms12564
    DOI: 10.1038/ncomms12564
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    Cited by:

    1. Richard J. Hewitt & Franz Puttur & David C. A. Gaboriau & Frédéric Fercoq & Maryline Fresquet & William J. Traves & Laura L. Yates & Simone A. Walker & Philip L. Molyneaux & Samuel V. Kemp & Andrew G., 2023. "Lung extracellular matrix modulates KRT5+ basal cell activity in pulmonary fibrosis," Nature Communications, Nature, vol. 14(1), pages 1-20, December.

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