Journal
NATURE MEDICINE
Volume 23, Issue 11, Pages 1287-+Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/nm.4417
Keywords
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Funding
- Science and Technology Research Promotion Program for Agriculture, Forestry, Fisheries and Food Industry
- AMED-CREST, AMED
- PRIME, AMED
- Ono Medical Research Foundation
- Cosmetology Research Foundation
- [21790060]
- [16H02613]
- [16K15122]
- [23227004]
- [17H06164]
- [15H05905]
- [17H06418]
- Grants-in-Aid for Scientific Research [15H05898, 15H04648, 17H06413, 15H05897, 16K15122, 17H05053, 15H05905] Funding Source: KAKEN
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Critical to the function of mast cells in immune responses including allergy is their production of lipid mediators, among which only omega-6 (v-6) arachidonate-derived eicosanoids have been well characterized. Here, by employing comprehensive lipidomics, we identify omega-3 (omega-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 omega-3 epoxides, leading to attenuated mast cell activation and anaphylaxis following Fc epsilon R1 cross-linking. Mechanistically, the omega-3 epoxides promote IgE-mediated activation of mast cells by downregulating Srcin1, a Src-inhibitory protein that counteracts Fc. RI signaling, through a pathway involving PPAR gamma. Thus, the PAF-AH2-omega-3 epoxide-Srcin1 axis presents new potential drug targets for allergic diseases.
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