先天免疫系统
炎症
生物
过敏性炎症
细胞生物学
先天性淋巴细胞
免疫学
细胞因子
半胱氨酸蛋白酶
信号转导
医学
过敏
哮喘
过敏原
作者
Michael Brusilovsky,Mark Rochman,Yrina Rochman,Julie M. Caldwell,Lydia E Mack,Jennifer M Felton,Jeff E. Habel,Aleksey Porollo,Chandrashekhar Pasare,Marc E. Rothenberg
出处
期刊:Nature Immunology
[Springer Nature]
日期:2021-09-16
卷期号:22 (10): 1316-1326
被引量:14
标识
DOI:10.1038/s41590-021-01011-2
摘要
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.
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