The E3 Ligase VHL Controls Lung Inflammation by Regulating Epithelium-ILC2 Cross-talk

Abstract

Abstract Group 2 innate lymphoid cells (ILC2) are a specialized subset of lymphoid effector cells that play an important role in allergic inflammation in response to host-derived cytokines and alarmins. Pulmonary epithelium play a critical role in the initiation of type 2 immunity by production of cytokines, such as TSLP, IL-25 and IL-33 after exposure to allergens. However, the epithelium-derived signals and their regulatory mechanisms that directly regulate ILC2 remain unclear. Here we report that conditional deletion of the E3 ubiquitin ligase VHL in lung epithelial secretory club cells caused a selective increase of ILC2 under steady state and during pulmonary inflammation, resulting in exacerbated type 2 immune responses accompanied by increased eosinophil infiltration. VHL deficiency in lung epithelial cells upregulated the number and activity of ILC2, which was rescued by hypoxia-inducible factor 1α(HIF1α) ablation. Our findings indicate that VHL-HIF pathways control allergic inflammation in the lung epithelium by regulating ILC2, but the mechanisms of their regulation need to be identified.