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Loss of integrin αvβ6-mediated TGF-β activation causes Mmp12-dependent emphysema

Nature volume 422, pages 169–173 (2003)Cite this article

Abstract

Integrins are heterodimeric cell-surface proteins that regulate cell growth, migration and survival. We have shown previously that the epithelial-restricted integrin αvβ6 has another critical function; that is, it binds and activates latent transforming growth factor-β (TGF-β)1,2. Through a global analysis of pulmonary gene expression in the lungs of mice lacking this integrin (Itgb6 null mice) we have identified a marked induction of macrophage metalloelastase (Mmp12)—a metalloproteinase that preferentially degrades elastin and has been implicated in the chronic lung disease emphysema3. Here we report that Itgb6-null mice develop age-related emphysema that is completely abrogated either by transgenic expression of versions of the β6 integrin subunit that support TGF-β activation, or by the loss of Mmp12. Furthermore, we show that the effects of Itgb6 deletion are overcome by simultaneous transgenic expression of active TGF-β1. We have uncovered a pathway in which the loss of integrin-mediated activation of latent TGF-β causes age-dependent pulmonary emphysema through alterations of macrophage Mmp12 expression. Furthermore, we show that a functional alteration in the TGF-β activation pathway affects susceptibility to this disease.

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Figure 1: Spontaneous, progressive pulmonary emphysema in Itgb6- mice.
Figure 2: Transgenic expression of human ITGB6FL or ITGB6777T reduces Mmp12 expression, normalizes macrophage appearance and prevents the development of airspace enlargement in Itgb6- mice.
Figure 3: Transgenic expression of Tgfb1Cys-Ser223,225 normalizes alveolar macrophage appearance and reduces Mmp12 expression in Itgb6 mice.
Figure 4: Deletion of Mmp12 prevents spontaneous emphysema in Itgb6- mice but does not affect inflammation.

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Acknowledgements

This work was supported by grants from the NHLBI to D.G.M. and D.S., including a Program for Genomic Applications Grant (Baygenomics).

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Authors and Affiliations

  1. Lung Biology Center, Department of Medicine, San Francisco General Hospital, University of California, San Francisco, California, 94143, USA

    David G. Morris, Xiaozhu Huang, Yanli Wang & Dean Sheppard

  2. Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of California, San Francisco, California, 94143, USA

    David G. Morris, Gregory Dolganov & Dean Sheppard

  3. Department of Medicine, Division of Pulmonary and Critical Care Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, 15261, USA

    Naftali Kaminski

  4. Department of Medicine, Section of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Boston, Massachusetts, 02115, USA

    Steven D. Shapiro

  5. Laboratory of Cellular Carcinogenesis and Tumor Promotion, National Cancer Institute, Bethesda, Maryland, 20892, USA

    Adam Glick

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Correspondence to Dean Sheppard.

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Morris, D., Huang, X., Kaminski, N. et al. Loss of integrin αvβ6-mediated TGF-β activation causes Mmp12-dependent emphysema. Nature 422, 169–173 (2003). https://doi.org/10.1038/nature01413

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