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The 17,18-epoxyeicosatetraenoic acid-G protein-coupled receptor 40 axis ameliorates contact hypersensitivity by inhibiting neutrophil mobility in mice and cynomolgus macaques
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2018 (English)In: Journal of Allergy and Clinical Immunology, ISSN 0091-6749, E-ISSN 1097-6825, Vol. 142, no 2, p. 470-482.e12Article in journal (Refereed) Published
Abstract [en]

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-alpha 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.

Place, publisher, year, edition, pages
MOSBY-ELSEVIER , 2018. Vol. 142, no 2, p. 470-482.e12
Keywords [en]
17 18-Epoxyeicosatetraenoic acid, G protein-coupled receptor 40, omega 3 fatty acid, contact persensitivity, dermatitis, neutrophil
National Category
Immunology in the medical area
Identifiers
URN: urn:nbn:se:umu:diva-151058DOI: 10.1016/j.jaci.2017.09.053ISI: 000440664400016PubMedID: 29288079OAI: oai:DiVA.org:umu-151058DiVA, id: diva2:1247158
Available from: 2018-09-11 Created: 2018-09-11 Last updated: 2018-09-11Bibliographically approved

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Edlund, Helena

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