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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References
Munger, J. S. et al. The integrin αvβ6 binds and activates latent TGFβ1: a mechanism for regulating pulmonary inflammation and fibrosis. Cell 96, 319–328 (1999)
Pittet, J. F. et al. TGF-β is a critical mediator of acute lung injury. J. Clin. Invest. 107, 1537–1544 (2001)
Kaminski, N. et al. Global analysis of gene expression in pulmonary fibrosis reveals distinct programs regulating lung inflammation and fibrosis. Proc. Natl Acad. Sci. USA 97, 1778–1783 (2000)
Werb, Z. & Gordon, S. Elastase secretion by stimulated macrophages. Characterization and regulation. J. Exp. Med. 142, 361–377 (1975)
Shapiro, S. D. et al. Molecular cloning, chromosomal localization, and bacterial expression of a murine macrophage metalloelastase. J. Biol. Chem. 267, 4664–4671 (1992)
Belaaouaj, A. et al. Human macrophage metalloelastase. Genomic organization, chromosomal location, gene linkage, and tissue-specific expression. J. Biol. Chem. 270, 14568–14575 (1995)
Hautamaki, R. D., Kobayashi, D. K., Senior, R. M. & Shapiro, S. D. Requirement for macrophage elastase for cigarette smoke-induced emphysema in mice. Science 277, 2002–2004 (1997)
Agrez, M., Chen, A., Cone, R. I., Pytela, R. & Sheppard, D. The αvβ6 integrin promotes proliferation of colon carcinoma cells through a unique region of the beta 6 cytoplasmic domain. J. Cell Biol. 127, 547–556 (1994)
Huang, X. Z., Chen, A., Agrez, M. & Sheppard, D. A point mutation in the integrin β6 subunit abolishes both αvβ6 binding to fibronectin and receptor localization to focal contacts. Am. J. Respir. Cell. Mol. Biol. 13, 245–251 (1995)
Huang, X., Wu, J., Zhu, W., Pytela, R. & Sheppard, D. Expression of the human integrin β6 subunit in alveolar type II cells and bronchiolar epithelial cells reverses lung inflammation in β6 knockout mice. Am. J. Respir. Cell. Mol. Biol. 19, 636–642 (1998)
Feinberg, M. W. et al. Transforming growth factor-β 1 inhibits cytokine-mediated induction of human metalloelastase in macrophages. J. Biol. Chem. 275, 25766–25773 (2000)
Werner, F. et al. Transforming growth factor-β 1 inhibition of macrophage activation is mediated via Smad3. J. Biol. Chem. 275, 36653–36658 (2000)
Huang, X. Z. et al. Inactivation of the integrin β6 subunit gene reveals a role of epithelial integrins in regulating inflammation in the lung and skin. J. Cell Biol. 133, 921–928 (1996)
Wang, Z. et al. Interferon gamma induction of pulmonary emphysema in the adult murine lung. J. Exp. Med. 192, 1587–1600 (2000)
Fujita, M. et al. Overexpression of tumour necrosis factor-α produces an increase in lung volumes and pulmonary hypertension. Am. J. Physiol. Lung Cell Mol. Physiol. 280, L39–L49 (2001)
Zheng, T. et al. Inducible targeting of IL-13 to the adult lung causes matrix metalloproteinase- and cathepsin-dependent emphysema. J. Clin. Invest. 106, 1081–1093 (2000)
Wert, S. E. et al. Increased metalloproteinase activity, oxidant production, and emphysema in surfactant protein D gene-inactivated mice. Proc. Natl Acad. Sci. USA 97, 5972–5977 (2000)
Leco, K. J. et al. Spontaneous air space enlargement in the lungs of mice lacking tissue inhibitor of metalloproteinases-3 (TIMP-3). J. Clin. Invest. 108, 817–829 (2001)
Kasahara, Y. et al. Inhibition of VEGF receptors causes lung cell apoptosis and emphysema. J. Clin. Invest. 106, 1311–1319 (2000)
Niewoehner, D. E., Kleinerman, J. & Rice, D. B. Pathologic changes in the peripheral airways of young cigarette smokers. N. Engl. J. Med. 291, 755–758 (1974)
Silverman, E. K. et al. Genetic epidemiology of severe, early-onset chronic obstructive pulmonary disease. Risk to relatives for airflow obstruction and chronic bronchitis. Am. J. Respir. Crit. Care Med. 157, 1770–1778 (1998)
Wikenheiser, K. A., Clark, J. C., Linnoila, R. I., Stahlman, M. T. & Whitsett, J. A. Simian virus 40 large T antigen directed by transcriptional elements of the human surfactant protein C gene produces pulmonary adenocarcinomas in transgenic mice. Cancer Res. 52, 5342–5352 (1992)
Cone, R. I., Weinacker, A., Chen, A. & Sheppard, D. Effects of beta subunit cytoplasmic domain deletions on the recruitment of the integrin αvβ6 to focal contacts. Cell Adhes. Commun. 2, 101–113 (1994)
Clark, J. C. et al. FGF-10 disrupts lung morphogenesis and causes pulmonary adenomas in vivo. Am. J. Physiol. Lung. Cell. Mol. Physiol. 280, L705–L715 (2001)
Liu, X. et al. Conditional epidermal expression of TGF beta 1 blocks neonatal lethality but causes a reversible hyperplasia and alopecia. Proc. Natl Acad. Sci. USA 98, 9139–9144 (2001)
Dolganov, G. M. et al. A novel method of gene transcript profiling in airway biopsy homogenates reveals increased expression of a Na+-K+-Cl- cotransporter (NKCC1) in asthmatic subjects. Genome Res. 11, 1473–1483 (2001)
Dunnill, M. S. Quantitative methods in the study of pulmonary pathology. Thorax 17, 320–328 (1962)
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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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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DOI: https://doi.org/10.1038/nature01413
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