Regnase-1 degradation is crucial for IL-33– and IL-25–mediated ILC2 activation

Matsushita, K., Tanaka, H., Yasuda, K., Adachi, T., Fukuoka, A. , Akasaki, S., Koida, A., Kuroda, E., Akira, S. and Yoshimoto, T. (2020) Regnase-1 degradation is crucial for IL-33– and IL-25–mediated ILC2 activation. JCI Insight, 5(4), e131480. (doi: 10.1172/jci.insight.131480) (PMID:31990689) (PMCID:PMC7101157)

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Abstract

Group 2 innate lymphoid cells (ILC2s) are a critical innate source of type 2 cytokines in allergic inflammation. Although ILC2s are recognized as a critical cell population in the allergic inflammation, the regulatory mechanism(s) of ILC2s are less well understood. Here, we show that Regnase-1, an immune regulatory RNAse that degrades inflammatory mRNAs, negatively regulates ILC2 function and that IκB kinase (IKK) complex–mediated Regnase-1 degradation is essential for IL-33– and IL-25–induced ILC2 activation. ILC2s from Regnase-1AA/AA mice expressing a Regnase-1 S435A/S439A mutant resistant to IKK complex–mediated degradation accumulated Regnase-1 protein in response to IL-33 and IL-25. IL-33– and IL-25–stimulated Regnase-1AA/AA ILC2s showed reduced cell proliferation and type 2 cytokine (IL-5, IL-9, and IL-13) production and increased cell death. In addition, Il2ra and Il1rl1, but not Il5, Il9, or Il13, mRNAs were destabilized in IL-33–stimulated Regnase-1AA/AA ILC2s. In vivo, Regnase-1AA/AA mice showed attenuated acute type 2 pulmonary inflammation induced by the instillation of IL-33, IL-25, or papain. Furthermore, the expulsion of Nippostrongylus brasiliensis was significantly delayed in Regnase-1AA/AA mice. These results demonstrate that IKK complex–mediated Regnase-1 degradation is essential for ILC2-mediated type 2 responses both in vitro and in vivo. Therefore, controlling Regnase-1 degradation is a potential therapeutic target for ILC2-contributed allergic disorders.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Suzuki, Dr Ayumi
Authors: Matsushita, K., Tanaka, H., Yasuda, K., Adachi, T., Fukuoka, A., Akasaki, S., Koida, A., Kuroda, E., Akira, S., and Yoshimoto, T.
College/School:College of Medical Veterinary and Life Sciences > School of Infection & Immunity
Journal Name:JCI Insight
Publisher:American Society for Clinical Investigation
ISSN:2379-3708
ISSN (Online):2379-3708

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