| Yoshinori Fukui | Last modified date：2024.05.24 |
Professor /
Division of Immunogenetics
Department of Immunobiology and Neuroscience
Medical Institute of Bioregulation
Department of Immunobiology and Neuroscience
Medical Institute of Bioregulation
Graduate School
Administration Post
Other
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Homepage
https://kyushu-u.elsevierpure.com/en/persons/yoshinori-fukui
Reseacher Profiling Tool Kyushu University Pure
http://www.bioreg.kyushu-u.ac.jp/iden/
Phone
092-642-6828
Fax
092-642-6829
Academic Degree
Doctor of Medical Science
Country of degree conferring institution (Overseas)
No
Field of Specialization
Immunogenetics, Molecular Immunology, Cell Biology
Total Priod of education and research career in the foreign country
03years00months
Outline Activities
Remodeling of the actin cytoskeleton is a fundamental biological response that regulates various cellular functions in the immune system. The aim of my research is to elucidate the mechanism by which remodeling of the actin cytoskeleton is induced in lymphoid and myeloid cells downstream of various receptors, and to define its relevance to cellular functions. This accomplishment will lead to the development of new therapeutics for intractable diseases such as autoimmune diseases, graft rejection and infectious diseases.
Research
Research Interests
- Remodeling of the actin cytoskeleton in the immune system
keyword : cytoskeleton, cell migration, antigen recognition, development of the immune system, G proteins
2001.01Remodeling of the actin cytoskeleton is a fundamental biological response that regulates various cellular functions in the immune system. The aim of this study is to elucidate the mechanism by which remodeling of the actin cytoskeleton is induced in lymphoid and myeloid cells following the stimulation of various receptors, and to define its relevance to cellular functions. This accomplishment will lead to the development of new therapeutics for intractable diseases such as autoimmune diseases, graft rejection and infectious diseases..
Reports
Papers
| 1. | Kenji Morino, Kazufumi Kunimura, Yuki Sugiura, Yoshihiro Izumi, Keisuke Matsubara, Sayaka Akiyoshi, Rae Maeda, Kenichiro Hirotani, Daiji Sakata, Seiya Mizuno, Satoru Takahashi, Takeshi Bamba, Takehito Uruno, Yoshinori Fukui, Cholesterol sulfate limits neutrophil recruitment and gut inflammation during mucosal injury., Front. Immunol., 2023.03, [URL]. |
| 2. | Kazufumi Kunimura , Sayaka Akiyoshi, Takehito Uruno, Keisuke Matsubara, Daiji Sakata, Kenji Morino, Kenichiro Hirotani, Yoshinori Fukui, DOCK2 regulates MRGPRX2/B2-mediated mast cell degranulation and drug-induced anaphylaxis., J. Allergy Clin. Immunol., 2023.02, [URL], Background: Drug-induced anaphylaxis is triggered by the direct stimulation of mast cells (MCs) via Mas-related G protein?coupled receptor X2 (MRGPRX2; mouse ortholog MRGPRB2). However, the precise mechanism that links MRGPRX2/B2 to MC degranulation is poorly understood. Dedicator of cytokinesis 2 (DOCK2) is a Rac activator predominantly expressed in hematopoietic cells. Although DOCK2 regulates migration and activation of leukocytes, its role in MCs remains unknown. Objective: We aimed to elucidate whether?and if so, how?DOCK2 is involved in MRGPRX2/B2-mediated MC degranulation and anaphylaxis. Methods: Induction of drug-induced systemic and cutaneous anaphylaxis was compared between wild-type and DOCK2-deficient mice. In addition, genetic or pharmacologic inactivation of DOCK2 in human and murine MCs was used to reveal its role in MRGPRX2/B2-mediated signal transduction and degranulation. Results: Induction of MC degranulation and anaphylaxis by compound 48/80 and ciprofloxacin was severely attenuated in the absence of DOCK2. Although calcium influx and phosphorylation of several signaling molecules were unaffected, MRGPRB2-mediated Rac activation and phosphorylation of p21-activated kinase 1 (PAK1) were impaired in DOCK2-deficient MCs. Similar results were obtained when mice or MCs were treated with small-molecule inhibitors that bind to the catalytic domain of DOCK2 and inhibit Rac activation. Conclusion: DOCK2 regulates MRGPRX2/B2-mediated MC degranulation through Rac activation and PAK1 phosphorylation, thereby indicating that the DOCK2-Rac-PAK1 axis could be a target for preventing drug-induced anaphylaxis.. |
| 3. | Ho Namkoong, （他473名） Yoshinori Fukui, （他14名） Yukinori Okada, DOCK2 is involved in the host genetics and biology of severe COVID-19, Nature, 2022.08, [URL], Identifying the host genetic factors underlying severe COVID-19 is an emerging challenge1,2,3,4,5. Here we conducted a genome-wide association study (GWAS) involving 2,393 cases of COVID-19 in a cohort of Japanese individuals collected during the initial waves of the pandemic, with 3,289 unaffected controls. We identified a variant on chromosome 5 at 5q35 (rs60200309-A), close to the dedicator of cytokinesis 2 gene (DOCK2), which was associated with severe COVID-19 in patients less than 65 years of age. This risk allele was prevalent in East Asian individuals but rare in Europeans, highlighting the value of genome-wide association studies in non-European populations. RNA-sequencing analysis of 473 bulk peripheral blood samples identified decreased expression of DOCK2 associated with the risk allele in these younger patients. DOCK2 expression was suppressed in patients with severe cases of COVID-19. Single-cell RNA-sequencing analysis (n?=?61 individuals) identified cell-type-specific downregulation of DOCK2 and a COVID-19-specific decreasing effect of the risk allele on DOCK2 expression in non-classical monocytes. Immunohistochemistry of lung specimens from patients with severe COVID-19 pneumonia showed suppressed DOCK2 expression. Moreover, inhibition of DOCK2 function with CPYPP increased the severity of pneumonia in a Syrian hamster model of SARS-CoV-2 infection, characterized by weight loss, lung oedema, enhanced viral loads, impaired macrophage recruitment and dysregulated type I interferon responses. We conclude that DOCK2 has an important role in the host immune response to SARS-CoV-2 infection and the development of severe COVID-19, and could be further explored as a potential biomarker and/or therapeutic target.. |
| 4. | Kazufumi Kunimura, Kazuhiko Yamamura, Takeshi Nakahara, Makiko Kido-Nakahara, Takehito Uruno, Yoshinori Fukui, Identification of a functional DOCK8 gene polymorphism associated with atopic dermatitis, Allergy, 2022.07, [URL], Atopic dermatitis (AD) is a chronic inflammatory skin disease characterized by recurrent eczematous lesions, intense itch, and type 2 immune responses. Interleukin 31 (IL-31) is a cytokine mainly produced from skin-homing CLA+ T cells. IL-31 plays a major role in AD pathogenesis. Dedicator of cytokinesis 8 (DOCK8) is an evolutionarily conserved guanine nucleotide exchange factor (GEF) for Cdc42. Bi-allelic loss-of-function mutations of DOCK8 cause a combined immunodeficiency characterized by AD. We have previously shown that knock down of DOCK8 gene in T cells from healthy controls markedly increases T-cell receptor-mediated IL31 gene expression. Therefore, DOCK8 acts as a negative regulator for IL-31 induction in human T cells. However, DOCK8 expression is comparable between healthy controls and AD patients, and functional significance of DOCK8 in the disease predisposition remains unknown. In this study, we found that DOCK8 polymorphism at position 1790 (rs17673268) is associated with the susceptibility to AD and revealed its underlying molecular basis. Although this study used a relatively small sample size, our findings provide a novel insight into AD pathogenesis.. |
| 5. | Takaaki Tatsuguchi, Takehito Uruno, Yuki Sugiura, Kounosuke Oisaki, Daisuke Takaya, Daiji Sakata, Yoshihiro Izumi, Takaya Togo, Yuko Hattori, Kazufumi Kunimura, Tetsuya Sakurai, Teruki Honma, Takeshi Bamba, Masafumi Nakamura, Motomu Kanai, Makoto Suematsu, Yoshinori Fukui, Pharmacological intervention of cholesterol sulfate-mediated T cell exclusion promotes antitumor immunity, Biochem. Biophys. Res. Commun., 2022.06, [URL]. |
| 6. | Takaaki Tatsuguchi, Takehito Uruno, Yuki Sugiura, Daiji Sakata, Yoshihiro Izumi, Tetsuya Sakurai, Yuko Hattori, Eiji Oki, Naoto Kubota, Koshiro Nishimoto, Masafumi Oyama, Kazufumi Kunimura, Takuto Ohki, Takeshi Bamba, Hideaki Tahara, Michiie Sakamoto, Masafumi Nakamura, Makoto Suematsu, Yoshinori Fukui, Cancer-derived cholesterol sulfate is a key mediator to prevent tumor infiltration by effector T cells., Int. Immunol. , 2022.04, [URL]. |
| 7. | Kazufumi Kunimura, Yoshinori Fukui, The molecular basis for IL-31 production and IL-31-mediated itch transmission: from biology to drug development., Int. Immunol., 33, 736, 2021.09, [URL]. |
| 8. | Keisuke Matsubara, Kazufumi Kunimura, Nana Yamane, Ryosuke Aihara, Tetsuya Sakurai, Daiji Sakata, Takehito Uruno, Yoshinori Fukui, DOCK8 dificiency causes a skewing to type 2 immunity in the gut with expansion of group 2 innate lymphoid cells., Biochem. Biophys. Res. Commun., 559, 140, 2021.06, [URL]. |
| 9. | Yasuhisa Kamikaseda, Takehito Uruno, Kazufumi Kunimura, Akihito Harada, Kuniko Saiki, Kounosuke Oisaki, Daiji Sakata, Takeshi Nakahara, Makiko Kido-Nakahara, Motomu Kanai, Seiji Nakamura, Yasuyuki Ohkawa, Masutaka Furue, Yoshinori Fukui, Target inhibition of EPAS1-driven IL-31 production by a small-molecule compound., J. Allergy Clin. Immun., 148, 638-in press, 2021.04, [URL], Background: IL-31 is a major pruritogen associated with atopic dermatitis (AD). Although a specific antibody for IL-31 receptor has been shown to alleviate pruritus in patients with AD, therapeutic approaches to inhibit IL-31 production remain unexploited. IL-31 production by helper T cells critically depends on the transcription factor EPAS1, which mediates IL31 promoter activation in collaboration with SP1. Objective: We aimed at developing small-molecule inhibitors that selectively block IL-31 production by helper T cells. Methods: We generated the reporter cell line that inducibly expressed EPAS1 in the presence of doxycycline to mediate Il31 promoter activation, and screened 9,600 chemical compounds. The selected compounds were further examined using helper T cells from a spontaneous mouse model of AD and those from patients with AD. Results: We have identified 4-(2-(4-isopropylbenzylidene)hydrazineyl)benzoic acid (IPHBA) as an inhibitor of IL-31 induction. Although IPHBA did not affect non-specific T cell proliferation, IPHBA inhibited antigen?induced IL-31 production by helper T cells from both an AD mouse model and AD patients, without affecting other cytokine productions and hypoxic responses. In line with this, itch responses induced by adoptive transfer of IL-31-producing helper T cells were attenuated when mice were orally treated with IPHBA. Mechanistically, IPHBA inhibited association between EPAS1 and SP1, resulting in defective recruitment of both transcription factors to the specific sites of IL31 promoter. We also determined the structure?activity relationship of IPHBA by synthesizing and analyzing 201 analog compounds. Conclusion: IPHBA could be a potential drug lead to inhibit EPAS1-driven IL-31 production.. |
| 10. | Ryosuke Aihara, Kazufumi Kunimura, Mayuki Watanabe, Takehito Uruno, Nana Yamane, Tetsuya Sakurai, Daiji Sakata, Fusanori Nishimura, Yoshinori Fukui, DOCK8 controls survival of group 3 innate lymphoid cells in the gut through Cdc42 activation., Int. Immunol. , 33, 160, 2021.03, [URL]. |
| 11. | Tetsuya Sakurai, Mutsuko Kunimoto-Niino, Kazufumi Kunimura, Nana Yamane, Daiji Sakata, Ryosuke Aihara, Tomoharu Yasuda, Shigeyuki Yokoyama, Mikako Shirouzu, Yoshinori Fukui, Takehito Uruno, A conserved PI(4,5)P2-binding domain is critical for immune regulatory function of DOCK8., Life Sci. Alliance, 4, 4, e202000873, 2021.02, [URL]. |
| 12. | Kazufumi Kunimura, Daiji Sakata, Xin Tun, Takehito Uruno, Miho Ushijima, Tomoya Katakai, Akira Shiraishi, Ryosuke Aihara, Yasuhisa Kamikaseda, Keisuke Matsubara, Hirokazu Kanegane, Shinichiro Sawa, Gerard Eberl, Shouichi Ohga, Yasunobu Yoshikai, Yoshinori Fukui, S100A4 Protein Is Essential for the Development of Mature Microfold Cells in Peyer's Patches, Cell Rep., 26, 9, 28340000000, 2019.11, [URL]. |
| 13. | Daiji Sakata, Takehito Uruno, Keisuke Matsubara, Tsugunobu Andoh, Kazuhiko Yamamura, Yuki Magoshi, Kazufumi Kunimura, Yasuhisa Kamikaseda, Masutaka Furue, Yoshinori Fukui, Selective role of neurokinin B in IL-31-induced itch response in mice, J. Allergy. Clin. Immunol., 144, 4, 113300000000, 2019.10, [URL], Atopic dermatitis (AD) is a chronic inflammatory skin disease characterized by recurrent eczematous legions and intense itch. Itch can be induced by various chemical mediators. Among them, much attention has been paid to interleukin 31 (IL-31) as an AD-associated itch mediator since the discovery of the pruritogenic action of IL-31 in mice. IL-31 is mainly produced by CD4+ T cells and transmits the signals via a heterodimeric receptor composed of IL-31 receptor A (IL-31RA) and oncostatin M receptor (OSMR), both of which are expressed in dorsal root ganglion (DRG) neurons. However, the neuronal mechanism underlying IL-31?induced itch sensation is poorly understood. By analyzing a mouse model for atopic dermatitis, we found that the expression of Tac2, which encodes neurokinin B (NKB), markedly increased in the DRG neurons in response to IL-31. While NKB-deficient mice lost IL-31?induced itch response, scratching behaviors induced by other pruritogens such as histamine, chloroquine and protease-activated receptor 2 (PAR2) agonist were unaffected in the absence of NKB. NKB transmits the signal through neurokinin 3 receptor (NK3R), a G protein-coupled tachykinin receptor. When wild-type mice were pre-treated with NK3R antagonists, IL-31?induced scratching was significantly attenuated, without affecting itch responses induced by other pruritogens. These results indicate that NKB-NK3R axis could be a novel therapeutic target controlling IL-31?induced itch in AD patients.. |
| 14. | Kazufumi Kunimura, Takehito Uruno, Yoshinori Fukui, DOCK-family proteins : key players in immune surveillance mechanisms, Int. Immunol., 2019.10, [URL]. |
| 15. | Tetsuya Sakurai, Takehito Uruno, Takaaki Tatsuguchi, Kazuhiko Yamamura, Miho Ushijima, Yuko Hattori, Mutsuko Kukimoto-Niino, Chiemi Mishima-Tsumagari, Mayuki Watanabe, Makoto Suematsu, Yoshinori Fukui, Cholesterol sulfate is a DOCK2 inhibitor that mediates tissue-specific immune evasion in the eye, Sci. Signal. , 11, 541, 2018.07, [URL], Although immune responses are essential to protect the body from infection, they can also harm tissues. Certain tissues and organs, including the eye, constitute specialized microenvironments that locally inhibit immune reactivity. Dedicator of cytokinesis protein 2 (DOCK2) is a Rac-specific guanine nucleotide exchange factor (GEF) that is predominantly found in hematopoietic cells. DOCK2 plays a key role in immune surveillance because it is essential for the activation and migration of leukocytes. DOCK2 mutations cause severe immunodeficiency in humans. We found that DOCK2-mediated Rac activation and leukocyte migration were effectively inhibited by cholesterol sulfate (CS), but not by cholesterol or other sulfated steroids. CS bound to the catalytic domain of DOCK2 and suppressed its GEF activity. Mass spectrometric quantification revealed that CS was most abundantly produced in the Harderian gland, which provides the lipids that form the oily layer of the tear film. Sulfation of cholesterol is mediated by the sulfotransferases SULT2B1b and, to a lesser extent, SULT2B1a, which are produced from the same gene through alternative splicing. By genetically inactivating Sult2b1, we showed that the lack of CS in mice augmented ultraviolet- and antigen-induced ocular surface inflammation, which was suppressed by administration of eye drops containing CS. Thus, CS is a naturally occurring DOCK2 inhibitor and contributes to the generation of the immunosuppressive microenvironment in the eye.. |
| 16. | Masutaka Furue, K. Yamamura, Makiko Nakahara, Takeshi Nakahara, Yoshinori Fukui, Emerging role of interleukin-31 and interleukin-31 receptor in pruritus in atopic dermatitis, Allergy: European Journal of Allergy and Clinical Immunology, 73, 1, 29-36, 36, 2018.01, [URL], Atopic dermatitis (AD) is a chronic or chronically relapsing, eczematous, severely pruritic skin disorder associated with skin barrier dysfunction. The lesional skin of AD exhibits T helper 2 (TH2)-deviated immune reactions. Interleukin-31 (IL-31), preferentially produced from TH2 cells, is a potent pruritogenic cytokine, and its systemic and local administration induces scratching behavior in rodents, dogs and monkeys. Recent clinical trials have revealed that administration of an anti-IL-31 receptor antibody significantly alleviates pruritus in patients with AD. In this review, we summarize recent topics related to IL-31 and its receptor with special references to atopic itch.. |
| 17. | Lauren A. Peters, Jacqueline Perrigoue, Arthur Mortha, Alina Iuga, Won Min Song, Eric M. Neiman, Sean R. Llewellyn, Antonio Di Narzo, Brian A. Kidd, Shannon E. Telesco, Yongzhong Zhao, Aleksandar Stojmirovic, Jocelyn Sendecki, Khader Shameer, Riccardo Miotto, Bojan Losic, Hardik Shah, Eunjee Lee, Minghui Wang, Jeremiah J. Faith, Andrew Kasarskis, Carrie Brodmerkel, Mark Curran, Anuk Das, Joshua R. Friedman, Yoshinori Fukui, Mary Beth Humphrey, Brian M. Iritani, Nicholas Sibinga, Teresa K. Tarrant, Carmen Argmann, Ke Hao, Panos Roussos, Jun Zhu, Bin Zhang, Radu Dobrin, Lloyd F. Mayer, Eric E. Schadt, A functional genomics predictive network model identifies regulators of inflammatory bowel disease, Nature Genetics, 49, 10, 1437-1449, 1449, 2017.10, [URL], A major challenge in inflammatory bowel disease (IBD) is the integration of diverse IBD data sets to construct predictive models of IBD. We present a predictive model of the immune component of IBD that informs causal relationships among loci previously linked to IBD through genome-wide association studies (GWAS) using functional and regulatory annotations that relate to the cells, tissues, and pathophysiology of IBD. Our model consists of individual networks constructed using molecular data generated from intestinal samples isolated from three populations of patients with IBD at different stages of disease. We performed key driver analysis to identify genes predicted to modulate network regulatory states associated with IBD, prioritizing and prospectively validating 12 of the top key drivers experimentally. This validated key driver set not only introduces new regulators of processes central to IBD but also provides the integrated circuits of genetic, molecular, and clinical traits that can be directly queried to interrogate and refine the regulatory framework defining IBD.. |
| 18. | Toyoshi Yanagihara, Takahiro Tomino, Takehito Uruno, Yoshinori Fukui, Thymic epithelial cell?specific deletion of Jmjd6 reduces Aire protein expression and exacerbates disease development in a mouse model of autoimmune diabetes, Biochemical and Biophysical Research Communications, 489, 1, 44055, 13, 2017.07, [URL], Thymic epithelial cells (TECs) establish spatially distinct microenvironments in which developing T cells are selected to mature or die. A unique property of medullary TECs is their expression of thousands of tissue-restricted self-antigens that is largely under the control of the transcriptional regulator Aire. We previously showed that Jmjd6, a lysyl hydroxylase for splicing regulatory proteins, is important for Aire protein expression and that transplantation of Jmjd6-deficient thymic stroma into athymic nude mice resulted in multiorgan autoimmunity. Here we report that TEC-specific deletion of Jmjd6 exacerbates development of autoimmune diabetes in a mouse model, which express both ovalbumin (OVA) under the control of the rat insulin gene promoter and OT-I T cell receptor specific for OVA peptide bound to major histocompatibility complex class I Kb molecules. We found that Aire protein expression in mTECs was reduced in the absence of Jmjd6, with retention of intron 2 in Aire transcripts. Our results thus demonstrate the importance of Jmjd6 in establishment of immunological tolerance in a more physiological setting.. |
| 19. | Hirotada Tajiri, Takehito Uruno, Takahiro Shirai, Daisuke Takaya, Shigeki Matsunaga, Daiki Setoyama, Mayuki Watanabe, Mutsuko Kukimoto-Niino, Kounosuke Oisaki, Miho Ushijima, Fumiyuki Sanematsu, Teruki Honma, Takaho Terada, Eiji Oki, Senji Shirasawa, Yoshihiko Maehara, Dongchon Kang, Jean Fran?ois C?t?, Shigeyuki Yokoyama, Motomu Kanai, Yoshinori Fukui, Targeting Ras-Driven Cancer Cell Survival and Invasion through Selective Inhibition of DOCK1, Cell Reports, 19, 5, 969-980, 980, 2017.05, [URL], Oncogenic Ras plays a key role in cancer initiation but also contributes to malignant phenotypes by?stimulating nutrient uptake and promoting invasive migration. Because these latter cellular responses require Rac-mediated remodeling of the actin cytoskeleton, we hypothesized that molecules involved in Rac activation may be valuable targets for cancer therapy. We report that genetic inactivation of the Rac-specific guanine nucleotide exchange factor DOCK1 ablates both macropinocytosis-dependent nutrient uptake and cellular invasion in Ras-transformed?cells. By screening chemical libraries, we have identified 1-(2-(3′-(trifluoromethyl)-[1,1′-biphenyl]-4-yl)-2-oxoethyl)-5-pyrrolidinylsulfonyl-2(1H)-pyridone (TBOPP) as a selective inhibitor of DOCK1. TBOPP dampened DOCK1-mediated invasion, macropinocytosis, and survival under the condition of glutamine deprivation without impairing the biological functions of the closely related DOCK2 and DOCK5 proteins. Furthermore, TBOPP treatment suppressed cancer metastasis and growth in?vivo in?mice. Our results demonstrate that selective pharmacological inhibition of DOCK1 could be a therapeutic approach to target cancer cell survival and invasion.. |
| 20. | Akira Shiraishi, Takehito Uruno, Fumiyuki Sanematsu, Miho Ushijima, Daiji Sakata, Toshiro Hara, Yoshinori Fukui, DOCK8 protein regulates macrophage migration through Cdc42 protein activation and LRAP35a protein interaction, Journal of Biological Chemistry, 292, 6, 2191-2202, 2202, 2017.02, [URL], DOCK8 is an atypical guanine nucleotide exchange factor for Cdc42, and its mutations cause combined immunodeficiency in humans. Accumulating evidence indicates that DOCK8 regulates the migration and activation of various subsets of leukocytes, but its regulatory mechanism is poorly understood. We here report that DOCK8-deficient macrophages exhibit a migration defect in a 2D setting. Although DOCK8 deficiency in macrophages did not affect the global Cdc42 activation induced by chemokine stimulation, rescue experiments revealed that the guanine nucleotide exchange factor activity of DOCK8 was required for macrophage migration. We found that DOCK8 associated with LRAP35a, an adaptor molecule that binds to the Cdc42 effector myotonic dystrophy kinase-related Cdc42-binding kinase, and facilitated its activity to phosphorylate myosin II regulatory light chain. When this interaction was disrupted in WT macrophages, they showed a migration defect, as seen in DOCK8-deficient macrophages. These results suggest that, during macrophage migration, DOCK8 links Cdc42 activation to actomyosin dynamics through the association with LRAP35a.. |
| 21. | Kazuhiko Yamamura, Takehito Uruno, Akira Shiraishi, Yoshihiko Tanaka, Miho Ushijima, Takeshi Nakahara, Mayuki Watanabe, Makiko Kido-Nakahara, Ikuya Tsuge, Masutaka Furue, Yoshinori Fukui, The transcription factor EPAS1 links DOCK8 deficiency to atopic skin inflammation via IL-31 induction, Nature communications, 8, 2017.01, [URL], 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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