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Omega-3 fatty acid epoxides are autocrine mediators that control the magnitude of IgE-mediated mast cell activation

Abstract

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.

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Figure 1: PAF-AH2 mediates spontaneous release of oxidized ω-3 fatty acids from mast cells.
Figure 2: Impaired antigen-induced anaphylaxis in Pafah2−/− mice.
Figure 3: PAF-AH2 facilitates FcɛRI-dependent activation of BMMCs.
Figure 4: ω-3 epoxides restore antigen-induced activation of Pafah2−/− mast cells in vitro and in vivo.
Figure 5: A PAF-AH2 inhibitor suppresses antigen-induced activation of mouse and human mast cells.
Figure 6: PAF-AH2-driven ω-3 epoxides downregulates Srcin1 expression via inhibiting PPARγ.

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Acknowledgements

We thank K. Mukai, Y. Takada, T. Fusuma (University of Tokyo) and T. Sakamoto (Nihon University School of Medicine) for their assistance and Y. Nozaki, M. Mikamoto (Eisai Co. Ltd.) and T. Imai (Kumamoto University) for their suggestions on the in vivo pharmacokinetic studies in mice. This work was supported by Grants-in-Aid for JSPS Research Fellow (Y.S.), for Young Scientists (B) (grant number 21790060 to N.K.), for Scientific Research (A) (grant number 16H02613 to M.M.), for Challenging Research (16K15122 to Y.T.), for Scientific Research (S) (grant numbers 23227004 and 17H06164 to H.A.) and for Scientific Research on Innovative Areas (grant numbers 15H05905 to M.M. and 17H06418 to H.A.); by the Science and Technology Research Promotion Program for Agriculture, Forestry, Fisheries and Food Industry (H.A.); by AMED-CREST, AMED (H.A. and M.M.); by PRIME, AMED (N.K.); by the Ono Medical Research Foundation (N.K.); and by the Cosmetology Research Foundation (N.K.).

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Y.S. and N.K. designed and performed the experiments, analyzed the data, interpreted the results and wrote the manuscript. Y. Taketomi performed the experiments with mast cell engraftment and interpreted the results. M.A. performed comprehensive lipidomics analysis. Y.O. aided in experiments with human mast cells. Y. Tanaka performed experiments with electroporation-mediated gene silencing. Y.N. performed microarray analysis. T.M. and H.K. performed pharmacokinetic studies and interpreted the results. A.A. and B.C. supplied reagents and interpreted the results. M.M. and H.A. designed the experiments, interpreted the results and wrote the manuscript.

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Correspondence to Makoto Murakami or Hiroyuki Arai.

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Shimanaka, Y., Kono, N., Taketomi, Y. et al. Omega-3 fatty acid epoxides are autocrine mediators that control the magnitude of IgE-mediated mast cell activation. Nat Med 23, 1287–1297 (2017). https://doi.org/10.1038/nm.4417

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