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

• Published in: Science immunology Vol. 5; no. 44
• Main Authors: Bitton, Almog, Avlas, Shmuel, Reichman, Hadar, Itan, Michal, Karo-Atar, Danielle, Azouz, Nurit P, Rozenberg, Perri, Diesendruck, Yael, Nahary, Limor, Rothenberg, Marc E, Benhar, Itai, Munitz, Ariel
• Format: Journal Article
• Language: English
• Published: United States 14-02-2020
• Subjects: Animals; Dermatitis, Atopic - chemically induced; Dermatitis, Atopic - immunology; Dinitrofluorobenzene; Female; Interleukin-13 - deficiency; Interleukin-13 - immunology; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Oxazolone; Receptors, Interleukin-4, Type II - immunology; Signal Transduction - immunology
• ISSN: 2470-9468
• DOI: 10.1126/sciimmunol.aaw2938

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
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.