17,18-EpETE–GPR40 axis ameliorates contact hypersensitivity by inhibiting neutrophil mobility in mice and cynomolgus macaques

Publication date: Available online 27 December 2017
Source:Journal of Allergy and Clinical Immunology
Author(s): 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, Soichiro Hirata, Pär Steneberg, Helena Edlund, Junken Aoki, Makoto Arita, Hiroshi Kiyono, Yasuhiro Yasutomi, Masaru Ishii, Kenji Kabashima, Jun Kunisawa
BackgroundMetabolites of eicosapentaenoic acid (EPA) exert various physiological actions. 17,18-epoxyeicosatetraenoic acid (17,18-EpETE) is a recently identified new class of anti-allergic and anti-inflammatory lipid metabolite of EPA, but its effects on skin inflammation and the underlying mechanisms remain to be investigated.ObjectiveWe evaluated the effectiveness of 17,18-EpETE for the control of contact hypersensitivity in mouse and cynomolgus macaques. We further sought to reveal underlying mechanisms by identifying the responsible receptor and cellular target of 17,18-EpETE.MethodsContact hypersensitivity was induced by topical application of 2,4-dinitrofluorobenzene. Skin inflammation and immune cell populations were analyzed by flow cytometric, immunohistologic and quantitative RT-PCR analyses. Neutrophil mobility was examined by imaging analysis in vivo and neutrophil culture in vitro. The receptor for 17,18-EpETE was identified by using the TGFα-shedding assay and receptor's involvement in the anti-inflammatory effects of 17,18-EpETE was examined by using KO mice and specific inhibitor treatment.ResultsWe 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 GPR40 (also known as free fatty acid receptor 1) and inhibited chemoattractant-induced Rac activation and pseudopod formation in neutrophils. Indeed, the anti-allergic inflammatory effect of 17,18-EpETE was abolished in the absence or inhibition of GPR40.Conclusion17,18-EpETE inhibits neutrophil mobility through the activation of GPR40, which is a potential therapeutic target to control allergic inflammatory diseases.

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