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.

环境过敏原，包括真菌、昆虫和螨虫，会触发 2 型免疫；然而，先天的感知机制和初始信号事件仍不清楚。在此，我们证明过敏原在上皮细胞中触发 RIPK1-caspase 8 核糖体激活。活性 caspase 8 随后与 caspase 3 和 7 结合，后者直接介导细胞内成熟和 IL-33 的释放，IL-33 是一种促特应性、先天免疫、警报素细胞因子。成熟的 IL-33 与同源 ST2 受体保持功能性相互作用，并在体外和体内引发有效的促过敏性炎症活性。药理学抑制 caspase 8 并删除鼠Il33和Casp8每种都减轻体内的过敏性炎症。临床数据证实核糖体激活和 IL-33 成熟可能是人类过敏性炎症的促成因素。我们的研究结果揭示了一种上皮屏障、过敏原感应机制，它作为细胞内分子信号平台汇聚在核糖体上，触发 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。