TY - JOUR
T1 - The transcription factor EPAS1 links DOCK8 deficiency to atopic skin inflammation via IL-31 induction
AU - Yamamura, Kazuhiko
AU - Uruno, Takehito
AU - Shiraishi, Akira
AU - Tanaka, Yoshihiko
AU - Ushijima, Miho
AU - Nakahara, Takeshi
AU - Watanabe, Mayuki
AU - Kido-Nakahara, Makiko
AU - Tsuge, Ikuya
AU - Furue, Masutaka
AU - Fukui, Yoshinori
N1 - Funding Information:
This research is supported by the Leading Advanced Projects for Medical Innovation (LEAP; to Y.F.) and the Research on Development of New Drugs (to Y.F.) from Japan Agency for Medical Research and Development (AMED); and Grants-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan (to Y.F.) and the Japan Society for the Promotion of Science (to Y.F.).
Publisher Copyright:
© The Author(s) 2017.
PY - 2017/1/9
Y1 - 2017/1/9
N2 - 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.
AB - 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.
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U2 - 10.1038/ncomms13946
DO - 10.1038/ncomms13946
M3 - Article
C2 - 28067314
AN - SCOPUS:85009154922
VL - 8
JO - Nature Communications
JF - Nature Communications
SN - 2041-1723
M1 - 13946
ER -