The αvβ6 integrin modulates airway hyperresponsiveness in mice by regulating intraepithelial mast cells
The αvβ6 integrin modulates airway hyperresponsiveness in mice by regulating intraepithelial mast cells
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DOI：
10.1172/jci58815
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发表时间：
2012-02-01
影响因子：
15.9
通讯作者：
Sheppard, Dean
中科院分区：
文献类型：
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作者：
Sugimoto, Kotaro;Kudo, Makoto;Sheppard, Dean
过敏性哮喘是最常见的哮喘形式，影响着1000多万美国人。虽然肥大细胞在过敏性哮喘的发病机制中起着关键作用，但它们在体内调节气道狭窄的机制仍不清楚。在这里，我们报告了缺乏αvβ6整合素的小鼠在过敏性哮喘模型中受到保护，使其免受过度气道狭窄的影响。呼吸道上皮细胞表达芯片显示肥大细胞蛋白水解酶是最显著的差异表达基因之一，其中小鼠肥大细胞蛋白酶1(mMCP-1)的表达在WT小鼠中由变应原刺激诱导，而mMCP-4、-5和-6在β6缺陷小鼠中的表达在基线水平上增加。这些发现很可能是由于失去了转化生长因子β的激活，因为上皮整合素αvβ6是潜伏的转化生长因子β的关键激活剂，而体外分化的肥大细胞表现出依赖于转化生长因子β的mMCP-1的表达和mMCP-4和6的抑制。在体外，mMCP-1增强小鼠气管环的收缩能力，这种作用依赖于完整的呼吸道上皮，而mMCP-4则抑制IL-β诱导的非上皮细胞依赖性的收缩作用。这些结果表明，整合素αvβ6上皮内激活的转化生长因子β通过调节肥大细胞蛋白水解酶的表达来调节气道反应性，这些蛋白水解酶及其蛋白分解底物可能成为改善过敏性哮喘治疗的新靶点。
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 alpha v beta 6 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 beta 6-deficient mice. These findings were most likely explained by loss of TGF-beta activation, since the epithelial integrin alpha v beta 6 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-beta-induced epithelial-independent enhancement of contractility. These results suggest that intraepithelial activation of TGF-beta by the alpha v beta 6 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.