Inhibiting the Notch signaling pathway suppresses Th17-associated airway hyperresponsiveness in obese asthmatic mice
Inhibiting the Notch signaling pathway suppresses Th17-associated airway hyperresponsiveness in obese asthmatic mice
复制标题
抑制 Notch 信号通路可抑制肥胖哮喘小鼠的 Th17 相关气道高反应性
DOI：
10.1038/s41374-019-0294-x
复制
发表时间：
2019-12-01
影响因子：
5
通讯作者：
Zhang, Weixi
中科院分区：
文献类型：
--
作者：
Zeng, Zeyu;Wang, Lei;Zhang, Weixi
Notch信号对哮喘和肥胖的调节至关重要。表达白细胞介素(IL)-17的CD4+ T细胞（Th17细胞）反应和气道高反应性（AHR）是哮喘和肥胖的关键特征。我们之前在哮喘小鼠模型中证明了抑制Notch信号通路可以减轻Th17的反应。然而，肥胖哮喘个体表现出Th17反应和AHR增加，其潜在机制目前尚不清楚。我们旨在评估Notch信号通路在肥胖哮喘小鼠中的功能，并确定抑制Notch信号通路的γ-分泌酶抑制剂（GSI）对Th17反应和AHR调节的影响。采用卵清蛋白（OVA）诱导C57BL/6小鼠哮喘，高脂饮食（HFD）诱导小鼠饮食性肥胖（DIO）。然后在dio - ova诱导的小鼠中经鼻给药GSI 7天。结果显示，肥胖哮喘小鼠Notch1和hes家族bHLH转录因子1 (Hes1) mRNA水平和Notch受体胞内结构域（NICD）蛋白水平升高。此外，这些小鼠的Th17细胞比例、血清IL-17A、IL-6和IL-1β水平、黏液蛋白5AC (MUC5AC) mRNA水平、视黄酸相关孤儿受体-γt (RORγt) mRNA和蛋白水平均增加，AHR严重程度增加。有趣的是，GSI处理导致dio - ova诱导小鼠Notch1和Hes1 mRNA和NICD蛋白水平降低，Th17细胞比例和IL-17A数量减少，AHR减轻。这些数据强烈表明Notch通路在肥胖哮喘小鼠中起关键作用。此外，抑制Notch通路可改善肥胖哮喘小鼠的AHR和Th17反应。
Notch signaling is crucial for the regulation of asthma and obesity. The interleukin (IL)-17-expressing CD4+ T cell (Th17 cell) response and airway hyperresponsiveness (AHR) are critical features of both asthma and obesity. We previously demonstrated that inhibiting the Notch signaling pathway alleviates the Th17 response in a mouse model of asthma. However, obese asthmatic individuals show increased Th17 responses and AHR, with the underlying mechanism not currently understood. We aimed to assess the function of Notch signaling in obese mice with asthma and to determine the impact of a γ-secretase inhibitor (GSI), which inhibits the Notch signaling pathway, on the regulation of the Th17 response and AHR. C57BL/6 mice were administered ovalbumin (OVA) to induce asthma, while a high-fat diet (HFD) was used to induce mouse diet-induced obesity (DIO). GSI was then administered intranasally for 7 days in DIO-OVA-induced mice. The results showed increased Notch1 and hes family bHLH transcription factor 1 (Hes1) mRNA levels and Notch receptor intracellular domain (NICD) protein levels in obese asthmatic mice. Furthermore, these mice showed an increased proportion of Th17 cells, serum IL-17A, IL-6, and IL-1β levels, mucin 5AC (MUC5AC) mRNA level, retinoic acid-related orphan receptor-γt (RORγt) mRNA and protein levels, and increased AHR severity. Interestingly, GSI treatment resulted in reduced Notch1 and Hes1 mRNA and NICD protein levels in DIO-OVA-induced mice, with a decreased Th17 cell proportion and IL-17A quantity and alleviated AHR. These data strongly indicate that the Notch pathway is critical in obese asthmatic mice. In addition, inhibiting the Notch pathway ameliorates AHR and the Th17 response in obese mice with asthma.