美国辛辛那提儿童医院Marc E. Rothenberg团队发现环境过敏原通过激活ripoptosome引发2型炎症。该项研究成果发表在2021年9月16日出版的《自然—免疫学》上。

研究人员证明过敏原会引发上皮细胞中的RIPK1-caspase 8ripoptosome 激活。活性半胱天冬酶8随后与半胱天冬酶3和7结合，直接介导细胞内成熟和IL-33(一种原特应性、先天免疫、警报细胞因子)的释放。成熟的IL-33持续与同源ST2受体相互作用，并在体外和体内引发有效的原特应性炎症活性。利用药物抑制caspase 8和敲除小鼠IL33和Casp8均能减轻过敏性炎症。临床数据证实ripoptosome激活和 IL-33成熟是导致人类过敏性炎症的可能因素。

该研究结果揭示了一种上皮屏障、过敏原感应机制，它们通过聚集ripoptosome作为细胞内分子信号平台，诱发2型先天免疫反应。这些发现对理解和治疗人类过敏性疾病具有重要意义。

据介绍，环境过敏原，包括真菌、昆虫和螨虫会引起2型免疫。然而，对环境过敏原的先天感知机制和初始信号仍不清楚。

附：英文原文

Title: Environmental allergens trigger type 2 inflammation through ripoptosome activation

Author: Brusilovsky, Michael, Rochman, Mark, Rochman, Yrina, Caldwell, Julie M., Mack, Lydia E., Felton, Jennifer M., Habel, Jeff E., Porollo, Aleksey, Pasare, Chandrashekhar, Rothenberg, Marc E.

Issue&Volume: 2021-09-16

Abstract: Environmental allergens, including fungi, insects and mites, trigger type 2 immunity; however, the innate sensing mechanisms and initial signaling events remain unclear. Herein, we demonstrate that allergens trigger RIPK1–caspase 8 ripoptosome activation in epithelial cells. The active caspase 8 subsequently engages caspases 3 and 7, which directly mediate intracellular maturation and release of IL-33, a pro-atopy, innate immunity, alarmin cytokine. Mature IL-33 maintained functional interaction with the cognate ST2 receptor and elicited potent pro-atopy inflammatory activity in vitro and in vivo. Inhibiting caspase 8 pharmacologically and deleting murine Il33 and Casp8 each attenuated allergic inflammation in vivo. Clinical data substantiated ripoptosome activation and IL-33 maturation as likely contributors to human allergic inflammation. Our findings reveal an epithelial barrier, allergen-sensing mechanism that converges on the ripoptosome as an intracellular molecular signaling platform, triggering type 2 innate immune responses. These findings have significant implications for understanding and treating human allergic diseases.

DOI: 10.1038/s41590-021-01011-2

Source: https://www.nature.com/articles/s41590-021-01011-2