Dendritic cells are functionally relevant targets of IL-25 in allergic lung inflammation (HYP2P.320)

Abstract

Abstract Asthma is a chronic inflammatory disease of the airways, typically triggered by allergens and often associated with type 2 responses. Skewing towards type 2 inflammation is due to release of one or more of the cytokines IL-33, TSLP and IL-25 by epithelial cells upon encounter with allergens or helminthes or when stressed. All three cytokines stimulate innate lymphoid cells type 2 (ILC2) to rapidly produce the classic inflammatory type 2 cytokines IL-13 and IL-5, and administration of any one of these cytokines into lungs initiates a strong inflammatory asthma-like response. IL-25 is the only member of the IL-17 cytokine family involved in type 2 responses. To understand its contributions to allergic lung inflammation, we first investigated for mechanisms by which IL-25 initiates responses on its own. In addition to ILC2s, we unexpectedly found that lung resident dendritic cells (DCs) rapidly responded. To assess the relevance of this finding, we made use of mice in which IL-25 cannot signal DCs. Activation of DCs by IL-25 was required for production of IL-9 by T cells, a cytokine linked to asthma as well. Importantly, IL-25-mediated activation of DCs was also required for IL-9 production by T cells in the context of house dust mite (HDM)-induced pulmonary inflammation, a physiologic inducer of asthma in patients. Our findings identify lung resident DCs as novel and functionally relevant targets of IL-25, even in the context of the broadly acting HDM allergens.