Role of growth arrest-specific gene 6 in the development of fungal allergic airway disease in mice.
Role of growth arrest-specific gene 6 in the development of fungal allergic airway disease in mice.
复制标题
DOI：
10.1165/rcmb.2014-0049oc
复制
发表时间：
2014-10
影响因子：
6.4
通讯作者：
T. Shibata;U. Ismailoglu;N. Kittan;A. Moreira;A. Coelho;G. Chupp;S. Kunkel;N. Lukacs;C. Hogaboam
中科院分区：
文献类型：
--
作者：
T. Shibata;U. Ismailoglu;N. Kittan;A. Moreira;A. Coelho;G. Chupp;S. Kunkel;N. Lukacs;C. Hogaboam
生长抑制特异性基因（Gas）6是一种分泌型维生素K依赖性蛋白，通过激活酪氨酸激酶Tyro 3、Axl和Mertk受体发挥多效性作用，但其在过敏性气道疾病中的作用尚不清楚。我们研究了Gas 6在小鼠真菌过敏性气道疾病发展中的作用。在烟曲霉诱导的过敏性气道疾病期间，在Gas 6缺陷型（Gas 6-/-）和野生型（WT）小鼠以及重组Gas 6治疗的WT小鼠中评价免疫应答。与无哮喘的受试者相比，各种严重程度的成人临床哮喘患者的Gas 6血浆水平均显着升高。在真菌过敏性气道疾病的鼠模型中，在肺中观察到Axl和Mertk的蛋白表达增加。与患有真菌过敏性气道疾病的WT小鼠相比，Gas 6-/-小鼠的气道高反应性（AHR）、全肺Th 2细胞因子水平、杯状细胞化生和支气管周围纤维化得到改善。WT小鼠鼻内Gas 6给药对气道炎症和AHR具有不同的影响。具体地，总剂量为2 μg的外源性Gas 6（即，低剂量）显著增加全肺Th 2细胞因子水平和随后的AHR，而总剂量为7 μg的外源性Gas 6（即，高剂量）与适当的对照组相比显著抑制Th 1和Th 2细胞因子和AHR。在机制上，Gas 6通过其由髓样DC表达的最高亲和力受体Axl促进Th 2活化。与对照WT组相比，Gas 6的鼻内给药持续加重气道重塑。这些结果表明Gas 6增强了真菌过敏性气道疾病的几个特征。
Growth arrest-specific gene (Gas)6 is a secreted vitamin K-dependent protein with pleiotropic effects via activation of receptor tyrosine kinase Tyro3, Axl, and Mertk receptors, but little is known about its role in allergic airway disease. We investigated the role of Gas6 in the development of fungal allergic airway disease in mice. The immune response was evaluated in Gas6-deficient (Gas6-/-) and wild-type (WT) mice and in recombinant Gas6-treated WT mice during Aspergillus fumigatus-induced allergic airway disease. Gas6 plasma levels were significantly elevated in adult clinical asthma of all severities compared with subjects without asthma. In a murine model of fungal allergic airway disease, increased protein expression of Axl and Mertk were observed in the lung. Airway hyperresponsiveness (AHR), whole lung Th2 cytokine levels, goblet cell metaplasia, and peribronchial fibrosis were ameliorated in Gas6-/- mice compared with WT mice with fungal allergic airway disease. Intranasal Gas6 administration into WT mice had a divergent effect on airway inflammation and AHR. Specifically, a total dose of 2 μg of exogenous Gas6 (i.e., low dose) significantly increased whole lung Th2 cytokine levels and subsequent AHR, whereas a total dose of 7 μg of exogenous Gas6 (i.e., high dose) significantly suppressed Th1 and Th2 cytokines and AHR compared with appropriate control groups. Mechanistically, Gas6 promoted Th2 activation via its highest affinity receptor Axl expressed by myeloid DCs. Intranasal administration of Gas6 consistently exacerbated airway remodeling compared with control WT groups. These results demonstrate that Gas6 enhances several features of fungal allergic airway disease.