TY - JOUR
T1 - Environmental allergens trigger type 2 inflammation through ripoptosome activation
AU - Brusilovsky, Michael
AU - Rochman, Mark
AU - Rochman, Yrina
AU - Caldwell, Julie M.
AU - Mack, Lydia E.
AU - Felton, Jennifer M.
AU - Habel, Jeff E.
AU - Porollo, Aleksey
AU - Pasare, Chandrashekhar
AU - Rothenberg, Marc E.
N1 - Funding Information:
This work was supported in part by NIH grant no. R37 AI045898; the Campaign Urging Research for Eosinophilic Disease (CURED); the Sunshine Charitable Foundation and its supporters, Denise and David Bunning (M.E.R.); and by grant nos. R01 AI123176, R01 AI113125 and R01 CA231303 (C.P.). We thank S. Hottinger for medical writing assistance.
Publisher Copyright:
© 2021, The Author(s), under exclusive licence to Springer Nature America, Inc.
PY - 2021/10/1
Y1 - 2021/10/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85115210309&partnerID=8YFLogxK
U2 - 10.1038/s41590-021-01011-2
DO - 10.1038/s41590-021-01011-2
M3 - Article
C2 - 34531562
AN - SCOPUS:85115210309
SN - 1529-2908
VL - 22
SP - 1316
EP - 1326
JO - Nature Immunology
JF - Nature Immunology
IS - 10
ER -
