| First Author | Sugimoto K | Year | 2012 |
| Journal | J Clin Invest | Volume | 122 |
| Issue | 2 | Pages | 748-58 |
| PubMed ID | 22232213 | Mgi Jnum | J:184504 |
| Mgi Id | MGI:5424110 | Doi | 10.1172/JCI58815 |
| Citation | Sugimoto K, et al. (2012) The alphavbeta6 integrin modulates airway hyperresponsiveness in mice by regulating intraepithelial mast cells. J Clin Invest 122(2):748-58 |
| abstractText | Allergic asthma is the most common form of asthma, affecting more than 10 million Americans. Although it is clear that mast cells have a key role in the pathogenesis of allergic asthma, the mechanisms by which they regulate airway narrowing in vivo remain to be elucidated. Here we report that mice lacking alphavbeta6 integrin are protected from exaggerated airway narrowing in a model of allergic asthma. Expression microarrays of the airway epithelium revealed mast cell proteases among the most prominent differentially expressed genes, with expression of mouse mast cell protease 1 (mMCP-1) induced by allergen challenge in WT mice and expression of mMCP-4, -5, and -6 increased at baseline in beta6-deficient mice. These findings were most likely explained by loss of TGF-beta activation, since the epithelial integrin alphavbeta6 is a critical activator of latent TGF-beta, and in vitro-differentiated mast cells showed TGF-beta-dependent expression of mMCP-1 and suppression of mMCP-4 and -6. In vitro, mMCP-1 increased contractility of murine tracheal rings, an effect that depended on intact airway epithelium, whereas mMCP-4 inhibited IL-13-induced epithelial-independent enhancement of contractility. These results suggest that intraepithelial activation of TGF-beta by the alphavbeta6 integrin regulates airway responsiveness by modulating mast cell protease expression and that these proteases and their proteolytic substrates could be novel targets for improved treatment of allergic asthma. |
