| First Author | Holgado A | Year | 2023 |
| Journal | J Allergy Clin Immunol | PubMed ID | 36898482 |
| Mgi Jnum | J:335212 | Mgi Id | MGI:7468460 |
| Doi | 10.1016/j.jaci.2023.02.026 | Citation | Holgado A, et al. (2023) A20 is a master switch of IL-33 signaling in macrophages and determines IL-33-induced lung immunity. J Allergy Clin Immunol |
| abstractText | BACKGROUND: 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. OBJECTIVE: We sought to determine the role of A20 in the regulation of IL-33 signaling in macrophages and IL-33-induced lung immunity. METHODS: 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. RESULTS: 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-gamma 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. CONCLUSIONS: We reveal a novel role for A20 as a negative regulator of IL-33-induced STAT1 signaling and IFN-gamma production in macrophages, which determines lung immune responses. |
