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

BACKGROUND: IL-33 plays a major role in the pathogenesis of allergic diseases such as asthma and atopic dermatitis. Upon 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: Important questions remain regarding the mechanisms that determine whether IL-33 induces a type 1 or type 2 immune response. Here we focus on the role of A20 in the regulation of IL-33 signalling in macrophages and IL-33-induced lung immunity.

METHODS: We studied the immunological response in lungs of IL-33-treated mice that specifically lack A20 in myeloid cells. We also analysed IL-33 signalling in A20-deficient bone marrow derived macrophages.

RESULTS: IL-33-induced lung ILC2 expansion, type 2 cytokine production and eosinophilia was drastically reduced in the absence of macrophage A20 expression, while neutrophils and interstitial macrophages in lung were increased. In vitro, IL-33-mediated NF-κB activation was only weakly affected in A20-deficient macrophages. However, in the absence of A20, IL-33 gained the ability to activate STAT1 signalling 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.

CONCLUSION: We reveal a novel role for A20 as a negative regulator of IL-33-induced STAT1 signalling and IFN-γ production in macrophages, which determines lung immune responses.

CLINICAL IMPLICATIONS: Our findings may eventually help to identify strategies that allow a better stratification of patients, leading to enhanced treatment efficacy.