mTOR信号通路调控IL-17在激素抵抗性哮喘发病中的作用研究

IL-17 is known to be crucial in the pathogenesis of steroid resistant asthma（SRA） via recruiting neutrophils into the airways. However, the mechanism of IL-17 production in SRA remains poorly defined. Mammalian target of rapamycin (mTOR) is an important signaling molecule of immune regulation. We found that both T cells and NKT cells producing IL-17 were significantly increased in number while mTOR signaling pathway was overacted, and the mice displayed more severe airway inflammation than WT mice in a NKT cell-dependent airway hypersensitivity model. This project aims to 1) establish the mice model of SRA by intranasal injection of DO11.10 mice with ovalbumin, and 2) investigate the role of mTOR signaling pathway in SRA by using rapamycin. mTOR signaling pathway will be measured, and airway inflammation and IL-17 and related chemokines will be assessed. On the clinical aspect, mTOR signaling pathway in PBMC from patients with SRA will be measured, airway inflammatory cells will be quantified and differentials determined, and IL-17 and related chemokines will be evaluated. In conclusion, from the study proposed we anticipate to understand mechanistically the contribution of mTOR signaling pathway in IL-17 generation in SRA, potentially providing novel avenues to clinical management of the disease.

IL-17介导中性粒细胞浸润是激素抵抗性哮喘（SRA）发病的关键，而SRA病程中IL-17是如何被调控的目前还不清楚。雷帕霉素靶蛋白（mTOR）是重要的免疫调控信号分子，我们发现：mTORC1过度活化后T细胞和NKT细胞产生IL-17显著增加，小鼠易于诱发NKT细胞介导的气道炎症，我们推测mTOR可能通过调节T细胞和NKT细胞分化，最终调控炎症效应因子IL-17的产生，在SRA的发病中发挥作用。本项目拟通过卵清蛋白（OVA）直接激发DO11.10小鼠建立SRA动物模型，并于建模前后抑制mTOR活化，检测mTOR活化水平、评估气道炎症、IL-17及相关趋化因子含量；另一方面检测SRA病人PBMC和气道炎症细胞内mTOR活化水平，体外干预mTOR活化后评估IL-17及相关趋化因子水平。据此阐明mTOR信号通路在SRA发病中的作用地位和对IL-17产生的调控作用，并为SRA治疗提供新的干预靶点。