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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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.).

Author information

Author notes

    • Yuta Shimanaka
    •  & Nozomu Kono

    These authors contributed equally to this work.

Affiliations

  1. Laboratory of Health Chemistry, Graduate School of Pharmaceutical Sciences, University of Tokyo, Tokyo, Japan.

    • Yuta Shimanaka
    • , Nozomu Kono
    • , Yuki Tanaka
    •  & Hiroyuki Arai
  2. PRIME, Japan Agency for Medical Research and Development, Tokyo, Japan.

    • Nozomu Kono
  3. Laboratory of Microenvironmental and Metabolic Health Science, Center for Disease Biology and Integrative Medicine, Graduate School of Medicine, University of Tokyo, Tokyo, Japan.

    • Yoshitaka Taketomi
    •  & Makoto Murakami
  4. Lipid Metabolism Project, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan.

    • Yoshitaka Taketomi
    •  & Makoto Murakami
  5. Laboratory for Metabolomics, RIKEN Center for Integrative Medical Sciences, Kanagawa, Japan.

    • Makoto Arita
  6. Allergy and Immunology Project Team, Center for Institutional Research and Medical Education, Nihon University School of Medicine, Tokyo, Japan.

    • Yoshimichi Okayama
  7. Center for Basic Technology Research, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan.

    • Yasumasa Nishito
  8. Laboratory of Molecular Pharmacokinetics, Graduate School of Pharmaceutical Sciences, University of Tokyo, Tokyo, Japan.

    • Tatsuki Mochizuki
    •  & Hiroyuki Kusuhara
  9. Chemical Physiology, Scripps Research Institute, La Jolla, California, USA.

    • Alexander Adibekian
    •  & Benjamin F Cravatt
  10. AMED-CREST, Japan Agency for Medical Research and Development, Tokyo, Japan.

    • Makoto Murakami
    •  & Hiroyuki Arai

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Contributions

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.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Makoto Murakami or Hiroyuki Arai.

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https://doi.org/10.1038/nm.4417