PI3K/AKT/mTOR通路
自噬
炎症
医学
呼吸上皮
免疫学
基因敲除
气道
细胞生物学
上皮
癌症研究
生物
信号转导
病理
细胞凋亡
生物化学
外科
作者
Wen Li,Yinfang Wu,Yun Zhao,Zhouyang Li,Hạixia Chen,Lingling Dong,Huiwen Liu,Min Zhang,Yanping Wu,Jie-Sen Zhou,Juan Xiong,Yue Hu,Hua Wen,Bin Zhang,Minzhi Qiu,Qingling Zhang,Wei Chunhua,Mingchun Wen,Jing Han,Xiaobo Zhou
出处
期刊:Thorax
[BMJ]
日期:2020-10-18
卷期号:75 (12): 1047-1057
被引量:26
标识
DOI:10.1136/thoraxjnl-2019-213771
摘要
Introduction Airway epithelial cells are recognised as an essential controller for the initiation and perpetuation of asthmatic inflammation, yet the detailed mechanisms remain largely unknown. This study aims to investigate the roles and mechanisms of the mechanistic target of rapamycin (MTOR)–autophagy axis in airway epithelial injury in asthma. Methods We examined the MTOR–autophagy signalling in airway epithelium from asthmatic patients or allergic mice induced by ovalbumin or house dust mites, or in human bronchial epithelial (HBE) cells. Furthermore, mice with specific MTOR knockdown in airway epithelium and autophagy-related lc3b -/- mice were used for allergic models. Results MTOR activity was decreased, while autophagy was elevated, in airway epithelium from asthmatic patients or allergic mice, or in HBE cells treated with IL33 or IL13. These changes were associated with upstream tuberous sclerosis protein 2 signalling. Specific MTOR knockdown in mouse bronchial epithelium augmented, while LC3B deletion diminished allergen-induced airway inflammation and mucus hyperproduction. The worsened inflammation caused by MTOR deficiency was also ameliorated in lc3b -/- mice. Mechanistically, autophagy was induced later than the emergence of allergen-initiated inflammation, particularly IL33 expression. MTOR deficiency increased, while knocking out of LC3B abolished the production of IL25 and the eventual airway inflammation on allergen challenge. Blocking IL25 markedly attenuated the exacerbated airway inflammation in MTOR-deficiency mice. Conclusion Collectively, these results demonstrate that allergen-initiated inflammation suppresses MTOR and induces autophagy in airway epithelial cells, which results in the production of certain proallergic cytokines such as IL25, further promoting the type 2 response and eventually perpetuating airway inflammation in asthma.
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