MTOR suppresses autophagy-mediated production of IL25 in allergic airway inflammation
MTOR suppresses autophagy-mediated production of IL25 in allergic airway inflammation
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DOI：
10.1136/thoraxjnl-2019-213771
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发表时间：
2020-12-01
期刊：
影响因子：
10
通讯作者：
Chen, Zhihua
中科院分区：
文献类型：
--
作者：
Li, Wen;Wu, Yinfang;Chen, Zhihua
前言气道上皮细胞是哮喘炎症发生和持续的重要控制者，但其具体机制尚不清楚。本研究旨在探讨雷帕霉素（MTOR）-自噬轴在哮喘气道上皮损伤中的作用和机制。MethodsWe研究了MTOR-自噬信号在哮喘患者或卵清蛋白或屋尘螨诱导的过敏小鼠，或在人支气管上皮（HBE）细胞的气道上皮细胞。此外，小鼠特异性MTOR敲低气道上皮细胞和自噬相关的lc 3b（-/-）小鼠被用于过敏models.ResultsMTOR活性降低，而自噬升高，在气道上皮细胞从哮喘患者或过敏小鼠，或在HBE细胞用IL 33或IL 13治疗。这些变化与上游结节性硬化蛋白2信号传导有关。小鼠支气管上皮中特异性MTOR敲除增强，而LC 3B缺失减少了过敏原诱导的气道炎症和粘液过度产生。在lc 3b（-/-）小鼠中，由MTOR缺乏引起的恶化的炎症也得到改善。从机制上讲，自噬的诱导晚于过敏原引发的炎症的出现，特别是IL 33的表达。MTOR缺陷增加，而LC 3B敲除消除了IL 25的产生和过敏原激发的最终气道炎症。阻断IL 25显着衰减加重气道炎症MTOR缺陷mice.ConclusionCollectively，这些结果表明，过敏原引发的炎症抑制MTOR和诱导自噬在气道上皮细胞，这导致在某些促过敏细胞因子，如IL 25的生产，进一步促进2型反应，并最终使哮喘气道炎症永久化。
IntroductionAirway 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.MethodsWe 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.ResultsMTOR 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.ConclusionCollectively, 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.