Research ArticleALLERGY

A key role for IL-13 signaling via the type 2 IL-4 receptor in experimental atopic dermatitis

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Science Immunology  14 Feb 2020:
Vol. 5, Issue 44, eaaw2938
DOI: 10.1126/sciimmunol.aaw2938

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Dermatitis details

Type 2 inflammation mediated by IL-4 and IL-13 has key roles in atopic dermatitis (AD). IL-4 and IL-13 signal via the type 2 IL-4 receptor (R), but the contribution of this receptor to AD is not well understood. Bitton et al. now show that dermatitis symptoms and expression of TNF-α, CXCL1, and CCL11 were dependent on IL-13 signaling via the type 2 IL-4R in nonhematopoietic cells, and these responses could be inhibited by pharmacological blockade of IL-13Rα1. In contrast, IL-4 signaling via the type 1 IL-4R was required for IL-4 and CCL24 expression and eosinophilia. These results provide insight into the role of type 2 IL-4R in AD and how it may be potentially targeted for other allergic diseases.

Abstract

IL-13 and IL-4 are potent mediators of type 2–associated inflammation such as those found in atopic dermatitis (AD). IL-4 shares overlapping biological functions with IL-13, a finding that is mainly explained by their ability to signal via the type 2 IL-4 receptor (R), which is composed of IL-4Rα in association with IL-13Rα1. Nonetheless, the role of the type 2 IL-4R in AD remains to be clearly defined. Induction of two distinct models of experimental AD in Il13ra1−/− mice, which lack the type 2 IL-4R, revealed that dermatitis, including ear and epidermal thickening, was dependent on type 2 IL-4R signaling. Expression of TNF-α was dependent on the type 2 IL-4R, whereas induction of IL-4, IgE, CCL24, and skin eosinophilia was dependent on the type 1 IL-4R. Neutralization of IL-4, IL-13, and TNF-α as well as studies in bone marrow–chimeric mice revealed that dermatitis, TNF-α, CXCL1, and CCL11 expression were exclusively mediated by IL-13 signaling via the type 2 IL-4R expressed by nonhematopoietic cells. Conversely, induction of IL-4, CCL24, and eosinophilia was dependent on IL-4 signaling via the type 1 IL-4R expressed by hematopoietic cells. Last, we pharmacologically targeted IL-13Rα1 and established a proof of concept for therapeutic targeting of this pathway in AD. Our data provide mechanistic insight into the differential roles of IL-4, IL-13, and their receptor components in allergic skin and highlight type 2 IL-4R as a potential therapeutic target in AD and other allergic diseases such as asthma and eosinophilic esophagitis.

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