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.
- airway epithelium
- allergic lung disease
- asthma mechanisms
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WL, YW and YZ contributed equally.
Contributors ZC and HS designed and supervised the study; WL, YW, YZ, ZL, HC, HL, LD, MZ, YW, JZ, JX, YH and WH performed experiments; MQ, QZ, WH, BZ, JH, CW and MW assisted in collection of human samples; YW performed EM experiments; WL, YW, YZ and ZC prepared figures; WL, YW, YZ and ZC drafted manuscript; XZ, WQ, FY, SY, ZC, AMKC and HS analysed data and revised manuscript. All authors approved the final manuscript.
Funding This work was supported by the Major Project (81490532 to HS), the General Projects (31970826 to ZC, 81370126 to WL and 81570021 to HH) and the Key Project (81930003 to HS) from the National Natural Science Foundation of China, and the National Key Research and Development Plan of China (2016YFC0905800 and 2016YFA0501602).
Competing interests AMKC is a cofounder, stock holder and serves on the Scientific Advisory Board for Proterris, which develops therapeutic uses for carbon monoxide. AMKC also has a use patent on CO. No other authors have any conflicts of interests.
Patient consent for publication Not required.
Ethics approval All experimental protocols were approved by the Ethical Committee for Animal Studies at Zhejiang University.
Provenance and peer review Not commissioned; externally peer reviewed.
Data availability statement All data relevant to the study are included in the article or uploaded as supplementary information.
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