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 Fcϵ RI cross-linking. Mechanistically, the ω-3 epoxides promote IgE-mediated activation of mast cells by downregulating Srcin1, a Src-inhibitory protein that counteracts Fcϵ RI signaling, through a pathway involving PPARg. Thus, the PAF-AH2-ω-3 epoxide-Srcin1 axis presents new potential drug targets for allergic diseases.
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