Caspase-11促进过敏性气道炎症
2021/01/28
摘要
活化的含半胱氨酸的天冬氨酸蛋白水解酶（Caspase）-1和Caspase-11在焦亡过程中诱导炎性细胞死亡。本文发现在小鼠和人巨噬细胞中，前列腺素E2（PGE2）能够抑制Caspase-11依赖性的焦亡。PGE2抑制小鼠和人巨噬细胞以及过敏性炎症小鼠气道中Caspase-11的表达。值得注意的是，缺乏Caspase-11的小鼠很难构建出实验性过敏性气道炎症，而众所周知的是，PGE2对过敏性气道炎症有保护作用。野生型过敏气道炎症小鼠肺中Caspase-11表达升高。而吲哚美辛可阻断PGE2的产生，从而增强肺Caspase-11的表达，而前列腺E1类似物米索前列醇则抑制肺Caspase-11的表达。最后，哮喘患者肺泡巨噬细胞细胞中Caspase-4表达增加，Caspase-4即Caspase-11在人类中的同源物。本文的研究发现，PGE2是Caspase-11驱动焦亡的负向调节因子，并提示Caspase4/11是过敏性气道炎症的关键因素，且与哮喘的病理生理学相关。
(中日友好医院呼吸与危重症医学科 张清 摘译 林江涛 审校)
(Nat Commun. 2020 Feb 26;11(1):1055. doi: 10.1038/s41467-020-14945-2.)
Caspase-11 promotes allergic airway inflammation
Zbigniew Zasłona , Ewelina Flis , Mieszko M Wilk , Richard G Carroll , Eva M Palsson-McDermott , Mark M Hughes , Ciana Diskin , Kathy Banahan , Dylan G Ryan , Alexander Hooftman, Alicja Misiak , Jay Kearney , Gunter Lochnit , Wilhelm Bertrams , Timm Greulich , Bernd Schmeck , Oliver J McElvaney , Kingston H G Mills , Ed C Lavelle , Małgorzata Wygrecka , Emma M Creagh , Luke A J O'Neill
Abstract
Activated caspase-1 and caspase-11 induce inflammatory cell death in a process termed pyroptosis. Here we show that Prostaglandin E2 (PGE2) inhibits caspase-11-dependent pyroptosis in murine and human macrophages. PGE2 suppreses caspase-11 expression in murine and human macrophages and in the airways of mice with allergic inflammation. Remarkably, caspase-11-deficient mice are strongly resistant to developing experimental allergic airway inflammation, where PGE2 is known to be protective. Expression of caspase-11 is elevated in the lung of wild type mice with allergic airway inflammation. Blocking PGE2 production with indomethacin enhances, whereas the prostaglandin E1 analog misoprostol inhibits lung caspase-11 expression. Finally, alveolar macrophages from asthma patients exhibit increased expression of caspase-4, a human homologue of caspase-11. Our findings identify PGE2 as a negative regulator of caspase-11-driven pyroptosis and implicate caspase-4/11 as a critical contributor to allergic airway inflammation, with implications for pathophysiology of asthma.
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寡细胞型哮喘的异质性：前瞻性队列研究的层次聚类分析
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更年期妇女的激素替代疗法与哮喘发作：国家队列研究
