IL-18 receptor signaling regulates IL-17A expression in lung innate lymphoid cells during fungal allergen exposure 3410

Abstract Description Group 2 innate lymphoid cells (ILC2s) are critical players in promoting type 2 inflammation that is present in most forms of asthma. ILC2s are tissue resident cells that produce the cytokines IL-5 and IL-13 upon activation. While ILC subsets (ILC1-3) produce distinct cytokine profiles, functional plasticity between the groups has been shown to occur under specific microenvironments, especially by the presence of cytokines released from the surrounding cells. IL-18 is a member of the IL-1 family, and multiple genome-wide studies have linked IL-18/IL-18 receptor (IL-18R) to human asthma. Here, we found that IL-18 and IL-18R were upregulated along with IL-33 upon intranasal challenge with Alternaria alternata. Further, ILC2s from IL-18R knock out mice (IL-18R-/-), displayed significantly increased IL-17A production from lung ILC2s compared to the wild-type controls. Elevated IL-5 and IL-17A production from these previously described “inflammatory” ILC2s was accompanied by increased eosinophilia in the lungs of IL-18R-/- mice after Alternaria challenge. Together, our work identifies a novel role for IL-18 signaling in vivo in the regulation of IL-17A production from lung ILC2s. The increase of IL-17A along with type 2 cytokines exacerbated lung eosinophilia, suggesting that IL-18 plays an inhibitory role in limiting type 2/3 pathology. Ultimately, continued research into the mechanisms behind ILC plasticity may lead to novel therapeutics for the treatment of ILC-driven asthma. Funding Sources T.A.D. supported by NIH AI171795 and Veterans Affairs BLR&D BX005073. H.M.M. supported by NIH/NCI K99/R00 CA256526. Topic Categories Immediate Hypersensitivity, Asthma, and Allergic Responses (HYP)