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.
Kazufumi Matsushita, Hiroki Tanaka, Koubun Yasuda, Takumi Adachi, Ayumi Fukuoka, Shoko Akasaki, Atsuhide Koida, Etsushi Kuroda, Shizuo Akira, Tomohiro Yoshimoto
This file is in Adobe Acrobat (PDF) format. If you have not installed and configured the Adobe Acrobat Reader on your system.
PDFs are designed to be printed out and read, but if you prefer to read them online, you may find it easier if you increase the view size to 125%.
Many versions of the free Acrobat Reader do not allow Save. You must instead save the PDF from the JCI Online page you downloaded it from. PC users: Right-click on the Download link and choose the option that says something like "Save Link As...". Mac users should hold the mouse button down on the link to get these same options.