Chronic allergic lung inflammation drives ILC2 dysfunction and transdifferentiation to IL-17A-producing ILC3s, promoting emphysema development 2272

Abstract Description Group 2 innate lymphoid cells (ILC2s) are activated by epithelial alarmins like IL-33, IL-25, and TSLP and produce type 2 cytokines IL-5 and IL-13, leading to eosinophilia and mucus hyperproduction in allergic inflammation. However, their role in chronic allergic inflammation remains unclear. We established a chronic allergic lung inflammation mouse model using repeated intranasal Alternaria alternata and papain injections. In the first three weeks of treatment, ILC2s expanded and produced type 2 cytokines, causing lung eosinophilia and mucus production. However, after five weeks, ILC2 numbers decreased, produced less cytokines and proliferated minimally. FACS analysis showed a small population of TIGIT+ ILC2s that were unresponsive to IL-33 and IL-7, indicating dysfunction. Unexpectedly, ILC3s also expanded, and some ILCs expressed both GATA3 and Rorγt and produced IL-5 and IL-17, suggesting ILC2-ILC3 transdifferentiation. In IL-33-KO mice, ILC2 expansion and ILC3 increase were prevented, supporting this transdifferentiation hypothesis. Additionally, histology revealed peribronchial inflammation and emphysema in wild-type mice after five weeks of allergen exposure, suggesting a role of ILC3s in emphysema development. Emphysema was also observed in Rag-KO mice, further supporting the involvement of ILCs in this process. These findings suggest chronic inflammation induces ILC2 dysfunction and transdifferentiation, possibly contributing to COPD in chronic asthma patients. Funding Sources This research was supported by CIHR Topic Categories Immediate Hypersensitivity, Asthma, and Allergic Responses (HYP)