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Nat Med. 2017 Nov;23(11):1287-1297. doi: 10.1038/nm.4417. Epub 2017 Oct 9.

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

Author information

1
Laboratory of Health Chemistry, Graduate School of Pharmaceutical Sciences, University of Tokyo, Tokyo, Japan.
2
PRIME, Japan Agency for Medical Research and Development, Tokyo, Japan.
3
Laboratory of Microenvironmental and Metabolic Health Science, Center for Disease Biology and Integrative Medicine, Graduate School of Medicine, University of Tokyo, Tokyo, Japan.
4
Lipid Metabolism Project, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan.
5
Laboratory for Metabolomics, RIKEN Center for Integrative Medical Sciences, Kanagawa, Japan.
6
Allergy and Immunology Project Team, Center for Institutional Research and Medical Education, Nihon University School of Medicine, Tokyo, Japan.
7
Center for Basic Technology Research, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan.
8
Laboratory of Molecular Pharmacokinetics, Graduate School of Pharmaceutical Sciences, University of Tokyo, Tokyo, Japan.
9
Chemical Physiology, Scripps Research Institute, La Jolla, California, USA.
10
AMED-CREST, Japan Agency for Medical Research and Development, Tokyo, Japan.

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.

PMID:
29035365
DOI:
10.1038/nm.4417
[Indexed for MEDLINE]

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