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.
Laboratory of Immunoregulation and Vaccine Research, Tsukuba Primate Research Center, NIBIOHN, Tsukuba, Japan.
J Allergy Clin Immunol. 2018 Aug;142(2):470-484.e12. doi: 10.1016/j.jaci.2017.09.053. Epub 2017 Dec 27.
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.
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.
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.
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.
17,18-EpETE inhibits neutrophil mobility through GPR40 activation, which is a potential therapeutic target to control allergic inflammatory diseases.
二十碳五烯酸的代谢产物发挥各种生理作用。17,18-环氧二十碳四烯酸（17,18-EpETE）是一种新发现的具有抗过敏和抗炎作用的二十碳五烯酸脂质代谢产物，但它对皮肤炎症的影响及其潜在机制仍有待研究。
我们评估了 17,18-EpETE 控制小鼠和食蟹猴接触性超敏反应的效果。我们进一步通过鉴定 17,18-EpETE 的负责受体和细胞靶点来揭示潜在机制。
通过应用 2,4-二硝基氟苯诱导接触性超敏反应。通过流式细胞术、免疫组织化学和定量 RT-PCR 分析来分析皮肤炎症和免疫细胞群。通过体内成像分析和体外中性粒细胞培养来研究中性粒细胞的迁移。通过 TGF-α脱落测定来鉴定 17,18-EpETE 的受体，通过 KO 小鼠和特异性抑制剂处理来研究该受体在 17,18-EpETE 的抗炎作用中的参与。
我们发现，预防性或治疗性给予 17,18-EpETE 通过抑制小鼠和食蟹猴中性粒细胞的迁移来改善接触性超敏反应。17,18-EpETE 被 G 蛋白偶联受体（GPR）40（也称为游离脂肪酸受体 1）识别，并抑制趋化因子诱导的 Rac 激活和中性粒细胞的伪足形成。事实上，在缺乏或抑制 GPR40 的情况下，17,18-EpETE 的抗过敏炎症作用被消除。
17,18-EpETE 通过 GPR40 激活抑制中性粒细胞迁移，这是控制过敏性炎症性疾病的潜在治疗靶点。
