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

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