Critical to the function of mast cells in immune responses including allergy is their production of lipid mediators, among which only omega-6 (ω-6) arachidonate-derived eicosanoids have been well characterized. Here, by employing comprehensive lipidomics, we identify omega-3 (ω-3) fatty acid epoxides as new mast cell-derived lipid mediators and show that they are produced by PAF-AH2, an oxidized-phospholipid-selective phospholipase A2. Genetic or pharmacological deletion of PAF-AH2 reduced the steady-state production of ω-3 epoxides, leading to attenuated mast cell activation and anaphylaxis following FcɛRI cross-linking. Mechanistically, the ω-3 epoxides promote IgE-mediated activation of mast cells by downregulating Srcin1, a Src-inhibitory protein that counteracts FcɛRI signaling, through a pathway involving PPARg. Thus, the PAF-AH2-ω-3 epoxide-Srcin1 axis presents new potential drug targets for allergic diseases.

中文翻译：

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Omega-3脂肪酸环氧化物是控制IgE介导的肥大细胞活化程度的自分泌介体。

肥大细胞在包括变态反应在内的免疫反应中发挥功能的关键是脂质介体的产生，其中只有omega-6（ω-6）花生四烯酸酯衍生的类二十烷酸得到了很好的表征。在这里，通过采用全面的脂质组学，我们确定了omega-3（ω-3）脂肪酸环氧化物为新的肥大细胞衍生的脂质介体，并表明它们是由PAF-AH2（一种氧化的磷脂选择性磷脂酶A2）产生的。PAF-AH2的遗传或药理学缺失降低了ω-3环氧化物的稳态产生，导致FcɛRI交联后肥大细胞激活和过敏反应减弱。从机制上讲，ω-3环氧化物通过下调Srcin1（一种抑制FcɛRI信号传导的Src抑制蛋白），通过涉及PPARg的途径来促进IgE介导的肥大细胞活化。因此，