Environmental allergens trigger type 2 inflammation through ripoptosome activation

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

Research output: Contribution to journalArticlepeer-review

29 Scopus citations


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.

Original languageEnglish
Pages (from-to)1316-1326
Number of pages11
JournalNature Immunology
Issue number10
StatePublished - 1 Oct 2021
Externally publishedYes

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology


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