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
  • 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: [email protected].
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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