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

David G. Morris, Xiaozhu Huang, Naftali Kaminski, Yanli Wang, Steven D. Shapiro, Gregory Dolganov, Adam Glick and Dean Sheppard ()
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David G. Morris: University of California
Xiaozhu Huang: University of California
Naftali Kaminski: University of Pittsburgh
Yanli Wang: University of California
Steven D. Shapiro: Brigham and Women's Hospital
Gregory Dolganov: University of California
Adam Glick: National Cancer Institute
Dean Sheppard: University of California

Nature, 2003, vol. 422, issue 6928, 169-173

Abstract: 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.

Date: 2003
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DOI: 10.1038/nature01413

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