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; Yoshinori Fukui

doi:10.1038/ncomms13946

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

Nat Commun. 2017 Jan 9:8:13946. doi: 10.1038/ncomms13946.

Authors

Kazuhiko Yamamura^{1

2}, Takehito Uruno^{1

3}, Akira Shiraishi¹, Yoshihiko Tanaka⁴, Miho Ushijima¹, Takeshi Nakahara², Mayuki Watanabe¹, Makiko Kido-Nakahara², Ikuya Tsuge⁵, Masutaka Furue², Yoshinori Fukui^{1

3}

Affiliations

¹ Division of Immunogenetics, Department of Immunobiology and Neuroscience, Medical Institute of Bioregulation, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.
² Department of Dermatology, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.
³ Research Centre for Advanced Immunology, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.
⁴ Department of Functional Bioscience, Section of Infection Biology, Fukuoka Dental College, 2-15-1 Tamura, Sawara-ku, Fukuoka 814-0175, Japan.
⁵ Department of Pediatrics, School of Medicine, Fujita Health University, 1-98 Dengakugakubo, Kutsukake-cho, Toyoake 470-1192, Japan.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Active Transport, Cell Nucleus
Animals
Aryl Hydrocarbon Receptor Nuclear Translocator / genetics
Aryl Hydrocarbon Receptor Nuclear Translocator / immunology
Basic Helix-Loop-Helix Transcription Factors / deficiency
Basic Helix-Loop-Helix Transcription Factors / genetics*
Basic Helix-Loop-Helix Transcription Factors / immunology
CD4-Positive T-Lymphocytes / immunology*
CD4-Positive T-Lymphocytes / pathology
Cell Nucleus / immunology
Cell Nucleus / metabolism
Cytosol / immunology
Cytosol / metabolism
Dermatitis, Atopic / genetics*
Dermatitis, Atopic / immunology
Dermatitis, Atopic / pathology
Disease Models, Animal
Female
Gene Expression Regulation
Guanine Nucleotide Exchange Factors / deficiency
Guanine Nucleotide Exchange Factors / genetics*
Guanine Nucleotide Exchange Factors / immunology
Heterozygote
Immunoglobulin E / genetics
Immunoglobulin E / immunology
Interleukins / genetics*
Interleukins / immunology
Male
Mice
Mice, Knockout
Promoter Regions, Genetic
Protein Transport
Signal Transduction
Sp1 Transcription Factor / genetics
Sp1 Transcription Factor / immunology

Substances

Arnt protein, mouse
Basic Helix-Loop-Helix Transcription Factors
Dock8 protein, mouse
Guanine Nucleotide Exchange Factors
Interleukins
Sp1 Transcription Factor
interleukin-31, mouse
Aryl Hydrocarbon Receptor Nuclear Translocator
endothelial PAS domain-containing protein 1
Immunoglobulin E