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

Yuta Shimanaka, Nozomu Kono, Yoshitaka Taketomi, Makoto Arita, Yoshimichi Okayama, Yuki Tanaka, Yasumasa Nishito, Tatsuki Mochizuki, Hiroyuki Kusuhara, Alexander Adibekian, Benjamin F. Cravatt, Makoto Murakami, Hiroyuki Arai

Research output: Contribution to journalArticle

18 Citations (Scopus)

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 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.

Original languageEnglish
Pages (from-to)1287-1297
Number of pages11
JournalNature medicine
Volume23
Issue number11
DOIs
Publication statusPublished - 2017 Nov 1
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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    Shimanaka, Y., Kono, N., Taketomi, Y., Arita, M., Okayama, Y., Tanaka, Y., Nishito, Y., Mochizuki, T., Kusuhara, H., Adibekian, A., Cravatt, B. F., Murakami, M., & Arai, H. (2017). Omega-3 fatty acid epoxides are autocrine mediators that control the magnitude of IgE-mediated mast cell activation. Nature medicine, 23(11), 1287-1297. https://doi.org/10.1038/nm.4417