Department of Immunology, MOE & MOH Key Laboratory of Medical Molecular Virology, School of Basic Medical Sciences, Fudan University, Shanghai, China.
Department of Thoracic Surgery, Zhongshan Hospital, Fudan University, Shanghai, China.
J Exp Med. 2018 Sep 3;215(9):2397-2412. doi: 10.1084/jem.20172225. Epub 2018 Jul 18.
Allergic asthma is a chronic inflammatory disease primarily mediated by Th2 immune mechanisms. Numerous studies have suggested that early life exposure to lipopolysaccharide (LPS) is negatively associated with allergic asthma. One proposed mechanism invokes desensitization of lung epithelial cells by LPS. We report here that acyloxyacyl hydrolase (AOAH), a host lipase that degrades and inactivates LPS, renders mice more susceptible to house dust mite (HDM)-induced allergic asthma. Lung epithelial cells from mice are refractory to HDM stimulation, decreasing dendritic cell activation and Th2 responses. Antibiotic treatment that diminished commensal LPS-producing bacteria normalized responses to HDM, while giving LPS intrarectally ameliorated asthma. mouse feces, plasma, and lungs contained more bioactive LPS than did those of mice. By inactivating commensal LPS, AOAH thus prevents desensitization of lung epithelial cells. An enzyme that prevents severe lung inflammation/injury in Gram-negative bacterial pneumonia has the seemingly paradoxical effect of predisposing to a Th2-mediated airway disease.
过敏性哮喘是一种慢性炎症性疾病，主要由 Th2 免疫机制介导。许多研究表明，生命早期接触脂多糖（LPS）与过敏性哮喘呈负相关。一种提出的机制是 LPS 使肺上皮细胞脱敏。我们在这里报告，酰氧基酰基水解酶（AOAH），一种降解和失活 LPS 的宿主脂肪酶，使小鼠更容易患屋尘螨（HDM）诱导的过敏性哮喘。 小鼠的肺上皮细胞对 HDM 刺激无反应，减少树突状细胞的激活和 Th2 反应。抗生素治疗可减少共生 LPS 产生菌，使 小鼠对 HDM 的反应正常化，而直肠内给予 LPS 则可改善哮喘。 小鼠的粪便、血浆和肺部含有比 小鼠更多的生物活性 LPS。通过失活共生 LPS，AOAH 防止肺上皮细胞脱敏。一种在革兰氏阴性菌肺炎中防止严重肺部炎症/损伤的酶，具有一种看似矛盾的效果，即易患 Th2 介导的气道疾病。
