The transcription factor EPAS1 links DOCK8 deficiency to atopic skin inflammation via IL-31 induction

Kazuhiko Yamamura, Takehito Uruno, Akira Shiraishi, Yoshihiko Tanaka, Miho Ushijima, Takeshi Nakahara, Mayuki Watanabe, Makiko Kido-Nakahara, Ikuya Tsuge, Masutaka Furue and Yoshinori Fukui ()
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Kazuhiko Yamamura: Medical Institute of Bioregulation, Kyushu University
Takehito Uruno: Medical Institute of Bioregulation, Kyushu University
Akira Shiraishi: Medical Institute of Bioregulation, Kyushu University
Yoshihiko Tanaka: Section of Infection Biology, Fukuoka Dental College
Miho Ushijima: Medical Institute of Bioregulation, Kyushu University
Takeshi Nakahara: Graduate School of Medical Sciences, Kyushu University
Mayuki Watanabe: Medical Institute of Bioregulation, Kyushu University
Makiko Kido-Nakahara: Graduate School of Medical Sciences, Kyushu University
Ikuya Tsuge: School of Medicine, Fujita Health University
Masutaka Furue: Graduate School of Medical Sciences, Kyushu University
Yoshinori Fukui: Medical Institute of Bioregulation, Kyushu University

Nature Communications, 2017, vol. 8, issue 1, 1-13

Abstract: Abstract Mutations of DOCK8 in humans cause a combined immunodeficiency characterized by atopic dermatitis with high serum IgE levels. However, the molecular link between DOCK8 deficiency and atopic skin inflammation is unknown. Here we show that CD4+ T cells from DOCK8-deficient mice produce large amounts of IL-31, a major pruritogen associated with atopic dermatitis. IL-31 induction critically depends on the transcription factor EPAS1, and its conditional deletion in CD4+ T cells abrogates skin disease development in DOCK8-deficient mice. Although EPAS1 is known to form a complex with aryl hydrocarbon receptor nuclear translocator (ARNT) and control hypoxic responses, EPAS1-mediated Il31 promoter activation is independent of ARNT, but in collaboration with SP1. On the other hand, we find that DOCK8 is an adaptor and negative regulator of nuclear translocation of EPAS1. Thus, EPAS1 links DOCK8 deficiency to atopic skin inflammation via IL-31 induction in CD4+ T cells.

Date: 2017
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DOI: 10.1038/ncomms13946

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