A20 is a master switch of IL-33 signaling in macrophages and determines IL-33–induced lung immunity

• Published in: Journal of allergy and clinical immunology Vol. 152; no. 1; pp. 244 - 256.e4
• Main Authors: Holgado, Aurora, Liu, Zhuangzhuang, Aidarova, Aigerim, Mueller, Christina, Haegman, Mira, Driege, Yasmine, Kreike, Marja, Scott, Charlotte L., Afonina, Inna S., Beyaert, Rudi
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.07.2023
• Subjects: airway inflammation; allergic asthma; Animals; autoimmunity; Eosinophilia; IFN-γ; IL-33; Immunity, Innate; Interleukin-33; Lung - immunology; Lymphocytes; Macrophages; Mice; Mice, Knockout; mouse models; TNFAIP3; mouse models; airway inflammation; IM; STAT1; JNK; qRT-PCR; TNFAIP3; BMDM; AM; MAPK; IL-33; BAL; i.t; HDM; ILC2; NF-κB; macrophages; IFN-γ; TF; allergic asthma; autoimmunity; eosinophilia; TLR; DC
• ISSN: 0091-6749; 1097-6825; 1097-6825
• DOI: 10.1016/j.jaci.2023.02.026

IL-33 plays a major role in the pathogenesis of allergic diseases such as asthma and atopic dermatitis. On its release from lung epithelial cells, IL-33 primarily drives type 2 immune responses, accompanied by eosinophilia and robust production of IL-4, IL-5, and IL-13. However, several studies show that IL-33 can also drive a type 1 immune response. We sought to determine the role of A20 in the regulation of IL-33 signaling in macrophages and IL-33–induced lung immunity. We studied the immunologic response in lungs of IL-33–treated mice that specifically lack A20 in myeloid cells. We also analyzed IL-33 signaling in A20-deficient bone marrow–derived macrophages. IL-33–induced lung innate lymphoid cell type 2 expansion, type 2 cytokine production, and eosinophilia were drastically reduced in the absence of macrophage A20 expression, whereas neutrophils and interstitial macrophages in lungs were increased. In vitro, IL-33–mediated nuclear factor kappa B activation was only weakly affected in A20-deficient macrophages. However, in the absence of A20, IL-33 gained the ability to activate signal transducer and activator of transcription 1 (STAT1) signaling and STAT1-dependent gene expression. Surprisingly, A20-deficient macrophages produced IFN-γ in response to IL-33, which was fully STAT1-dependent. Furthermore, STAT1 deficiency partially restored the ability of IL-33 to induce ILC2 expansion and eosinophilia in myeloid cell–specific A20 knockout mice. We reveal a novel role for A20 as a negative regulator of IL-33–induced STAT1 signaling and IFN-γ production in macrophages, which determines lung immune responses.