ILC2-intrinsic IL-33 amplifies ILC2 activation and allergic lung inflammation

Interleukin-33 (IL-33) from lung epithelial cells serves as a crucial alarmin to activate the lung-resident group 2 innate lymphoid cells (ILC2s) and then to initiate type 2 inflammation. However, whether IL-33 has an intrinsic role in the ILC2-driven lung inflammation remains unclear. In this study, we characterize the proteomic features of mouse lung ILC2s during activation and observe an increased expression of intrinsic IL-33 in activated ILC2s. The expression of intrinsic IL-33 in lung ILC2s can be induced by the co-stimulation of cysteinyl leukotrienes (CysLTs) and exogenous IL-33. Deletion of ILC2-intrinsic IL-33 attenuates lung inflammation by restraining ILC2 proliferation and cytokine production. Mechanistically, ILC2-intrinsic IL-33 promotes transcriptional activation of both inflammatory and proliferative signaling cascades. Additionally, ILC2-intrinsic IL-33 localizes in the nucleus and promotes the expression of Fosl2 and Nfatc1 through promoting their chromatin accessibility, leading to increased ILC2 proliferation and type 2 cytokine production. Further, we confirm that intrinsic IL-33 can be induced by co-stimulation of CysLTs and exogenous IL-33 in human ILC2s (hILC2s), which is positively related to enhanced hILC2 responses. Collectively, our findings implicate IL-33 as a nuclear factor and intrinsic amplifier of lung-resident ILC2s, operating in a positive feedback loop downstream of exogenous IL-33 and CysLTs co-stimulation to promote allergic lung inflammation. IL-33 is known to promote differentiation and activation of innate lymphoid cells type 2 (ILC2). Here the authors show that IL-33 generated by ILC2 has a function in the increase of inflammatory allergic responses and can be promoted by exogenous IL-33 and cysteinyl leukotrienes.