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  3. The 17,18-epoxyeicosatetraenoic acid-G protein-coupled receptor 40 axis ameliorates contact hypersensitivity by inhibiting neutrophil mobility in mice and cynomolgus macaques

The 17,18-epoxyeicosatetraenoic acid-G protein-coupled receptor 40 axis ameliorates contact hypersensitivity by inhibiting neutrophil mobility in mice and cynomolgus macaques

  • J Allergy Clin Immunol. 2018 Aug;142(2):470-484.e12. doi: 10.1016/j.jaci.2017.09.053.
Takahiro Nagatake 1,  Yumiko Shiogama 2,  Asuka Inoue 3,  Junichi Kikuta 4,  Tetsuya Honda 5,  Prabha Tiwari 1,  Takayuki Kishi 3,  Atsushi Yanagisawa 4,  Yosuke Isobe 6,  Naomi Matsumoto 1,  Michiko Shimojou 1,  Sakiko Morimoto 1,  Hidehiko Suzuki 1,  So-Ichiro Hirata 7,  Pär Steneberg 8,  Helena Edlund 8,  Junken Aoki 3,  Makoto Arita 9,  Hiroshi Kiyono 10,  Yasuhiro Yasutomi 11,  Masaru Ishii 4,  Kenji Kabashima 5,  Jun Kunisawa 12
Affiliations

Affiliations

  • 1 Laboratory of Vaccine Materials, Center for Vaccine and Adjuvant Research, and Laboratory of Gut Environmental System, National Institutes of Biomedical Innovation, Health and Nutrition (NIBIOHN), Ibaraki, Japan.
  • 2 Laboratory of Immunoregulation and Vaccine Research, Tsukuba Primate Research Center, NIBIOHN, Tsukuba, Japan.
  • 3 Laboratory of Molecular and Cellular Biochemistry, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Japan.
  • 4 Department of Immunology and Cell Biology, Graduate School of Medicine and Frontier Biosciences, Japan.
  • 5 Department of Dermatology, Kyoto University Graduate School of Medicine, Kyoto, Japan.
  • 6 Laboratory for Metabolomics, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.
  • 7 Laboratory of Vaccine Materials, Center for Vaccine and Adjuvant Research, and Laboratory of Gut Environmental System, National Institutes of Biomedical Innovation, Health and Nutrition (NIBIOHN), Ibaraki, Japan; Department of Microbiology and Immunology, Kobe University Graduate School of Medicine, Kobe, Japan.
  • 8 Umea Center for Molecular Medicine, Umea University, Umea, Sweden.
  • 9 Laboratory for Metabolomics, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan; Graduate School of Medical Life Science, Yokohama City University, Tsurumi-ku, Yokohama, Japan; Division of Physiological Chemistry and Metabolism, Graduate School of Pharmaceutical Sciences, Keio University, Minato-ku, Tokyo, Japan.
  • 10 Division of Mucosal Immunology, Department of Microbiology and Immunology and International Research and Development Center for Mucosal Vaccines, Institute of Medical Science, University of Tokyo, Tokyo, Japan; Department of Immunology, Graduate School of Medicine, Chiba University, Chiba, Japan.
  • 11 Laboratory of Immunoregulation and Vaccine Research, Tsukuba Primate Research Center, NIBIOHN, Tsukuba, Japan; Division of Immunoregulation, Department of Molecular and Experimental Medicine, Mie University Graduate School of Medicine, Tsu, Japan.
  • 12 Laboratory of Vaccine Materials, Center for Vaccine and Adjuvant Research, and Laboratory of Gut Environmental System, National Institutes of Biomedical Innovation, Health and Nutrition (NIBIOHN), Ibaraki, Japan; Department of Microbiology and Immunology, Kobe University Graduate School of Medicine, Kobe, Japan; Division of Mucosal Immunology, Department of Microbiology and Immunology and International Research and Development Center for Mucosal Vaccines, Institute of Medical Science, University of Tokyo, Tokyo, Japan; Graduate School of Medicine, Graduate School of Pharmaceutical Sciences, Graduate School of Dentistry, Osaka University, Suita, Japan. Electronic address: kunisawa@nibiohn.go.jp.
PMID: 29288079 DOI: 10.1016/j.jaci.2017.09.053
Abstract

Background: Metabolites of eicosapentaenoic acid exert various physiologic actions. 17,18-Epoxyeicosatetraenoic acid (17,18-EpETE) is a recently identified new class of antiallergic and anti-inflammatory lipid metabolite of eicosapentaenoic acid, but its effects on skin inflammation and the underlying mechanisms remain to be investigated.

Objective: We evaluated the effectiveness of 17,18-EpETE for control of contact hypersensitivity in mice and cynomolgus macaques. We further sought to reveal underlying mechanisms by identifying the responsible receptor and cellular target of 17,18-EpETE.

Methods: Contact hypersensitivity was induced by topical application of 2,4-dinitrofluorobenzene. Skin inflammation and immune cell populations were analyzed by using flow cytometric, immunohistologic, and quantitative RT-PCR analyses. Neutrophil mobility was examined by means of imaging analysis in vivo and neutrophil culture in vitro. The receptor for 17,18-EpETE was identified by using the TGF-α shedding assay, and the receptor's involvement in the anti-inflammatory effects of 17,18-EpETE was examined by using KO mice and specific inhibitor treatment.

Results: We found that preventive or therapeutic treatment with 17,18-EpETE ameliorated contact hypersensitivity by inhibiting neutrophil mobility in mice and cynomolgus macaques. 17,18-EpETE was recognized by G protein-coupled receptor (GPR) 40 (also known as Free Fatty Acid Receptor 1) and inhibited chemoattractant-induced Rac activation and pseudopod formation in neutrophils. Indeed, the antiallergic inflammatory effect of 17,18-EpETE was abolished in the absence or inhibition of GPR40.

Conclusion: 17,18-EpETE inhibits neutrophil mobility through GPR40 activation, which is a potential therapeutic target to control allergic inflammatory diseases.

Keywords

17,18-Epoxyeicosatetraenoic acid; G protein–coupled receptor 40; contact hypersensitivity; dermatitis; neutrophil; ω3 fatty acid.

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