IL-33–Induced Atopic Dermatitis–Like Inflammation in Mice Is Mediated by Group 2 Innate Lymphoid Cells in Concert with Basophils

Abstract

IL-33 is a proinflammatory cytokine that plays a pivotal role in allergic disorders. In a transgenic mouse expressing IL-33 driven by a keratin-14 promoter (IL33tg), atopic dermatitis (AD)-like inflammation develops spontaneously with the activation of group 2 innate lymphoid cells (ILC2s). However, it remains unknown how effector cells, such as T helper type 2 cells, ILC2s, and basophils, contribute to the inflammatory process induced by IL-33. To address the question, we examined the phenotype of IL33tg mice lacking each of these cells. AD-like inflammation still developed in Rag2KO IL33tg mice lacking T and B cells; in contrast, when ILC2s were depleted in IL33tg mice via bone marrow transplantation from ILC2-lacking, RAR-related orphan receptor alpha-deficient mice, the development of AD-like inflammation was almost completely suppressed. Basophils were accumulated in the inflamed skin of IL33tg mice, and AD-like inflammation was alleviated by the conditional depletion of basophils using anti-FcεRIα antibodies or a Bas-TRECK transgenic mouse system. In these basophil-depleted IL33tg skins, ILC2s were decreased, and cytokines and chemokines such as IL-5, IL-13, and CCL5 were reduced. From these results, we suggest that IL-33-induced AD-like inflammation is dependent on innate immune responses that are mediated by ILC2s in concert with basophils.