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

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

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.

MeSH terms

  • 1-Alkyl-2-acetylglycerophosphocholine Esterase / genetics
  • Animals
  • Cells, Cultured
  • Culture Media, Conditioned
  • Epoxy Compounds / chemistry*
  • Fatty Acids, Omega-3 / chemistry
  • Fatty Acids, Omega-3 / pharmacology*
  • Humans
  • Immunoglobulin E / immunology*
  • Mast Cells / immunology*
  • Membrane Lipids / metabolism
  • Mice
  • Mice, Knockout
  • Phospholipids / metabolism

Substances

  • Culture Media, Conditioned
  • Epoxy Compounds
  • Fatty Acids, Omega-3
  • Membrane Lipids
  • Phospholipids
  • Immunoglobulin E
  • 1-Alkyl-2-acetylglycerophosphocholine Esterase
  • Pafah2 protein, mouse