Journal Article

Environmental allergens trigger type 2 inflammation through ripoptosome activation

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

2021

Overview

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. IL-33 plays a central role in type II immune responses and is generally thought to be released following cellular damage and processed extracellularly. Rothenberg and colleagues describe a new ripoptosome pathway that is assembled following exposure to various unrelated environmental allergens and that processes IL-33 into an active form intracellularly.

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: 631/250/127/1213 / 692/699/249/2510/9 / Adolescent / Allergens / Allergens - immunology / Allergic diseases / Allergies / Animals / Atopy / Biomedical and Life Sciences / Biomedicine / Caspase 8 - immunology / Caspase-8 / Cell activation / Cell Line / Cell Line, Tumor / Child / Child, Preschool / Cytokines - immunology / Epithelial cells / Epithelial Cells - immunology / Female / HEK293 Cells / Humans / Hypersensitivity / Hypersensitivity - immunology / Immune response / Immunity, Innate - immunology / Immunology / Infectious Diseases / Inflammation / Inflammation - immunology / Innate immunity / Interleukin-33 - immunology / Intracellular / Intracellular signalling / Male / Mice / Mice, Inbred BALB C / Mice, Inbred C57BL / Signal Transduction - immunology