Department of Pulmonary, Shanghai Children's Medical Center Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai, China.
Pediatr Allergy Immunol Pulmonol. 2020 Mar;33(1):25-32. doi: 10.1089/ped.2019.1088.
T helper 17 (Th17) is regarded as key immune cell in the pathogenesis of noneosinophilic asthma (NEA) due to the recruitment of neutrophils into the airways. The mammalian target of rapamycin (mTOR) is an important signaling molecule that plays a critical role in immune regulation. This study focused on mTOR signaling pathway in the regulation of Th17-mediated neutrophilic airway inflammation. Ovalbumin (OVA) T cell receptor transgenic DO11.10 mice (DO11.10 mice) were used to establish NEA model, and few mice received specific mTORC1 inhibitor rapamycin (RAPA) before intranasal administration of OVA. The severity of airway inflammation was determined by differential cell counts in bronchoalveolar lavage (BAL) fluids and histopathologic lung analysis. The levels of various cytokines in BAL fluids and lung tissues were measured. To determine the role of mTORC1 signaling in Th17 differentiation, naive T cells from wild-type (WT) and TSC1 knockout (KO) mice were cultured in Th17 skewing condition with or without RAPA and the production of IL-17A was compared. Treatment with RAPA markedly attenuated OVA-induced neutrophilic airway inflammation in DO11.10 mice. Also the production of IL-17A was inhibited without affecting the production of interferon-γ (IFN-γ) and IL-4 in lungs. Furthermore, RAPA suppressed differentiation of Th17 cells , whereas enhanced activity of mTORC1 promoted Th17 cell differentiation and increased the expression of Th17-related transcription factors RORγt and RORα. These results suggested that mTOR promoted Th17 cell polarization and enhanced OVA-induced neutrophilic airway inflammation in experimental NEA.
辅助性 T 细胞 17（Th17）被认为是无嗜酸性粒细胞性哮喘（NEA）发病机制中的关键免疫细胞，因为中性粒细胞被募集到气道中。哺乳动物雷帕霉素靶蛋白（mTOR）是一种重要的信号分子，在免疫调节中发挥着关键作用。本研究集中于 mTOR 信号通路在调节 Th17 介导的中性粒细胞性气道炎症中的作用。卵清蛋白（OVA）T 细胞受体转基因 DO11.10 小鼠（DO11.10 小鼠）用于建立 NEA 模型，并且在鼻内给予 OVA 之前，少数小鼠接受了特定的 mTORC1 抑制剂雷帕霉素（RAPA）。通过支气管肺泡灌洗液（BAL）中差异细胞计数和组织病理学肺分析来确定气道炎症的严重程度。测量 BAL 液和肺组织中各种细胞因子的水平。为了确定 mTORC1 信号在 Th17 分化中的作用，从野生型（WT）和 TSC1 敲除（KO）小鼠中分离出的幼稚 T 细胞在存在或不存在 RAPA 的情况下在 Th17 偏倚条件下培养，并比较了 IL-17A 的产生。 RAPA 治疗明显减轻了 DO11.10 小鼠中 OVA 诱导的中性粒细胞性气道炎症。同时，IL-17A 的产生受到抑制，而 IFN-γ（IFN-γ）和 IL-4 在肺部的产生不受影响。此外，RAPA 抑制了 Th17 细胞的分化，而 mTORC1 的活性增强促进了 Th17 细胞的分化，并增加了 Th17 相关转录因子 RORγt 和 RORα 的表达。 这些结果表明，mTOR 促进了 Th17 细胞的极化，并增强了实验性 NEA 中 OVA 诱导的中性粒细胞性气道炎症。
