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 FcεRI cross-linking. Mechanistically, the ω-3 epoxides promote IgE-mediated activation of mast cells by downregulating Srcin1, a Src-inhibitory protein that counteracts FcεRI 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：

---

Omega-3脂肪酸环氧化物是控制IgE介导的肥大细胞激活程度的自分泌介体

肥大细胞在包括过敏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 ）花生四烯酸衍生的类花生酸得到了很好的表征。在这里，通过采用综合脂质组学，我们确定了omega-3（ω -3 ）脂肪酸环氧化物是新的肥大细胞衍生的脂质介体，并表明它们是由PAF-AH2（一种氧化磷脂选择性磷脂酶A2）产生的。遗传或PAF-AH2的药理缺失减少了稳态生产的ω -3环氧化物，导致减毒的肥大细胞活化和过敏反应以下的Fc ε RI交联。从机械上讲，ω-3环氧化物促进肥大细胞的IgE介导的激活通过下调Srcin1，一个SRC-抑制蛋白抵消的Fc ε RI信令，通过一个通路涉及PPARG。因此，PAF-AH2– ω -3环氧化物–Srcin1轴为过敏性疾病提出了新的潜在药物靶标。