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

Takahiro Nagatake, Yumiko Shiogama, Asuka Inoue, Junichi Kikuta, Tetsuya Honda, Prabha Tiwari, Takayuki Kishi, Atsushi Yanagisawa, Yosuke Isobe, Naomi Matsumoto, Michiko Shimojou, Sakiko Morimoto, Hidehiko Suzuki, So ichiro Hirata, Pär Steneberg, Helena Edlund, Junken Aoki, Makoto Arita, Hiroshi Kiyono, Yasuhiro YasutomiMasaru Ishii, Kenji Kabashima, Jun Kunisawa

Research output: Contribution to journalArticle

11 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)470-484.e12
JournalJournal of Allergy and Clinical Immunology
Volume142
Issue number2
DOIs
Publication statusPublished - 2018 Aug

Keywords

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

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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    Nagatake, T., Shiogama, Y., Inoue, A., Kikuta, J., Honda, T., Tiwari, P., Kishi, T., Yanagisawa, A., Isobe, Y., Matsumoto, N., Shimojou, M., Morimoto, S., Suzuki, H., Hirata, S. I., Steneberg, P., Edlund, H., Aoki, J., Arita, M., Kiyono, H., ... Kunisawa, J. (2018). The 17,18-epoxyeicosatetraenoic acid–G protein–coupled receptor 40 axis ameliorates contact hypersensitivity by inhibiting neutrophil mobility in mice and cynomolgus macaques. Journal of Allergy and Clinical Immunology, 142(2), 470-484.e12. https://doi.org/10.1016/j.jaci.2017.09.053