The αvβ6 integrin modulates airway hyperresponsiveness in mice by regulating intraepithelial mast cells

Kotaro Sugimoto, et al., J. Clin. Invest. 2012, 122:748-58

Speaker: Ya-Ting Chu (朱雅婷)                                    Time: 15:10~16:00, Apr. 25, 2012

Commentator: Prof. Jiu-Yao Wang (王志堯老師)       Place: Room 601

Abstract

Allergic asthma is a common type of asthma. It belongs to a kind of chronic inflammatory disease in which exposure to allergens causes intermittent attacks of breathlessness, airway hyperresponsiveness, wheezing, coughing, and mucus metaplasia.  Mast cells are harmful factors in allergic inflammation and asthma. Previous studies indicated that mast cell degranulation is a common phenomenon in asthmatic lungs and some mast cell-derived mediators can also be found in bronchoalveolar lavage fluid from asthmatic patients. The infiltration of mast cells into the airway smooth muscle cell layer is a distinct feature of allergic asthma and is associated with airway hyperresponsiveness. Although it is clear that mast cells play a key role in the pathogenesis of allergic asthma, the mechanisms by which they regulate airway narrowing in vivo still need to be clarified. Furthermore, previous study indicated that the avβ6 integrin plays an important role in activating latent TGF-b in epithelial cells. Mice lacking avβ6 integrin are protected from pulmonary fibrosis and acute lung injury because they lack active TGF-b. In this study, the results showed that mice lacking avβ6 integrin are protected from airway narrowing in a model of allergic asthma. Microarray analysis of the airway epithelium revealed different gene expression between wild type and β6-deficient mice. Mouse mast cell protease (mMCP) -4, -5 and -6 were increased in saline-treated β6-deficient mice compared with wild type mice and mMCP-1 was induced by allergen challenge in wild type mice but not in β6-deficient mice . The in vitro data showed that TGF-b-dependent expression of mMCP-1 increased contractility of murine tracheal rings and suppressed mMCP-4 and -6expression. These results suggest that intraepithelial activation of TGF-b by avβ6 integrin regulates airway responsiveness by modulating mast cell protease expression. Therefore, these proteases may be targets for improved treatment of allergic asthma.

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