Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

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

Nature Medicine volume 23, pages 1287–1297 (2017)Cite this article

Subjects

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.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

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.

Similar content being viewed by others

Accession codes

Primary accessions

Gene Expression Omnibus

References

  1. Devereux, G. The increase in the prevalence of asthma and allergy: food for thought. Nat. Rev. Immunol. 6, 869–874 (2006).

    Article  CAS  PubMed  Google Scholar 

  2. Kalesnikoff, J. & Galli, S.J. New developments in mast cell biology. Nat. Immunol. 9, 1215–1223 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Serhan, C.N. Pro-resolving lipid mediators are leads for resolution physiology. Nature 510, 92–101 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Nagakura, T., Matsuda, S., Shichijyo, K., Sugimoto, H. & Hata, K. Dietary supplementation with fish oil rich in omega-3 polyunsaturated fatty acids in children with bronchial asthma. Eur. Respir. J. 16, 861–865 (2000).

    Article  CAS  PubMed  Google Scholar 

  5. Peat, J.K. et al. Three-year outcomes of dietary fatty acid modification and house dust mite reduction in the Childhood Asthma Prevention Study. J. Allergy Clin. Immunol. 114, 807–813 (2004).

    Article  CAS  PubMed  Google Scholar 

  6. Murakami, M. et al. Recent progress in phospholipase A2 research: from cells to animals to humans. Prog. Lipid Res. 50, 152–192 (2011).

    Article  CAS  PubMed  Google Scholar 

  7. Sugiyama, H. et al. Peroxisome proliferator–activated receptors are expressed in mouse bone marrow–derived mast cells. FEBS Lett. 467, 259–262 (2000).

    Article  CAS  PubMed  Google Scholar 

  8. Murakami, M., Matsumoto, R., Urade, Y., Austen, K.F. & Arm, J.P. c-Kit ligand mediates increased expression of cytosolic phospholipase A2, prostaglandin endoperoxide synthase-1, and hematopoietic prostaglandin D2 synthase and increased IgE-dependent prostaglandin D2 generation in immature mouse mast cells. J. Biol. Chem. 270, 3239–3246 (1995).

    Article  CAS  PubMed  Google Scholar 

  9. Fujishima, H. et al. Cytosolic phospholipase A2 is essential for both the immediate and the delayed phases of eicosanoid generation in mouse bone marrow–derived mast cells. Proc. Natl. Acad. Sci. USA 96, 4803–4807 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Uozumi, N. et al. Role of cytosolic phospholipase A2 in allergic response and parturition. Nature 390, 618–622 (1997).

    Article  CAS  PubMed  Google Scholar 

  11. Bae, K. et al. Platelet-activating factor (PAF)-dependent transacetylase and its relationship with PAF acetylhydrolases. J. Biol. Chem. 275, 26704–26709 (2000).

    CAS  PubMed  Google Scholar 

  12. Costello, P.S. et al. Critical role for the tyrosine kinase Syk in signalling through the high affinity IgE receptor of mast cells. Oncogene 13, 2595–2605 (1996).

    CAS  PubMed  Google Scholar 

  13. Nishida, K. et al. FcɛRI-mediated mast cell degranulation requires calcium-independent microtubule-dependent translocation of granules to the plasma membrane. J. Cell Biol. 170, 115–126 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Lee, J.H. et al. The Src family kinase Fgr is critical for activation of mast cells and IgE-mediated anaphylaxis in mice. J. Immunol. 187, 1807–1815 (2011).

    Article  CAS  PubMed  Google Scholar 

  15. Hong, H. et al. The Src family kinase Hck regulates mast cell activation by suppressing an inhibitory Src family kinase Lyn. Blood 110, 2511–2519 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Suzuki, R. et al. Molecular editing of cellular responses by the high-affinity receptor for IgE. Science 343, 1021–1025 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Matsuzawa, A., Hattori, K., Aoki, J., Arai, H. & Inoue, K. Protection against oxidative stress–induced cell death by intracellular platelet-activating factor–acetylhydrolase II. J. Biol. Chem. 272, 32315–32320 (1997).

    Article  CAS  PubMed  Google Scholar 

  18. Morisseau, C. & Hammock, B.D. Impact of soluble epoxide hydrolase and epoxyeicosanoids on human health. Annu. Rev. Pharmacol. Toxicol. 53, 37–58 (2013).

    Article  CAS  PubMed  Google Scholar 

  19. Stafforini, D.M. et al. Release of free F2-isoprostanes from esterified phospholipids is catalyzed by intracellular and plasma platelet-activating factor acetylhydrolases. J. Biol. Chem. 281, 4616–4623 (2006).

    Article  CAS  PubMed  Google Scholar 

  20. Adibekian, A. et al. Click-generated triazole ureas as ultrapotent in vivo–active serine hydrolase inhibitors. Nat. Chem. Biol. 7, 469–478 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Di Stefano, P. et al. p140Cap protein suppresses tumour cell properties, regulating Csk and Src kinase activity. EMBO J. 26, 2843–2855 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Latour, S. & Veillette, A. Proximal protein tyrosine kinases in immunoreceptor signaling. Curr. Opin. Immunol. 13, 299–306 (2001).

    Article  CAS  PubMed  Google Scholar 

  23. Li, J.P. et al. The phosphatase JKAP/DUSP22 inhibits T-cell receptor signalling and autoimmunity by inactivating Lck. Nat. Commun. 5, 3618 (2014).

    Article  PubMed  CAS  Google Scholar 

  24. Yoshioka, K. et al. Endothelial PI3K-C2α, a class II PI3K, has an essential role in angiogenesis and vascular barrier function. Nat. Med. 18, 1560–1569 (2012).

    Article  CAS  PubMed  Google Scholar 

  25. Taketomi, Y. et al. Mast cell maturation is driven via a group III phospholipase A2–prostaglandin D2–DP1 receptor paracrine axis. Nat. Immunol. 14, 554–563 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Vadas, P. et al. Platelet-activating factor, PAF acetylhydrolase, and severe anaphylaxis. N. Engl. J. Med. 358, 28–35 (2008).

    Article  CAS  PubMed  Google Scholar 

  27. Hercule, H.C. et al. The vasodilator 17,18-epoxyeicosatetraenoic acid targets the pore-forming BKα channel subunit in rodents. Exp. Physiol. 92, 1067–1076 (2007).

    Article  CAS  PubMed  Google Scholar 

  28. López-Vicario, C. et al. Inhibition of soluble epoxide hydrolase modulates inflammation and autophagy in obese adipose tissue and liver: role for omega-3 epoxides. Proc. Natl. Acad. Sci. USA 112, 536–541 (2015).

    Article  PubMed  CAS  Google Scholar 

  29. Zhang, G. et al. Epoxy metabolites of docosahexaenoic acid (DHA) inhibit angiogenesis, tumor growth, and metastasis. Proc. Natl. Acad. Sci. USA 110, 6530–6535 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Aldrovandi, M. et al. Human platelets generate phospholipid-esterified prostaglandins via cyclooxygenase-1 that are inhibited by low dose aspirin supplementation. J. Lipid Res. 54, 3085–3097 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Sugiyama, H. et al. Peroxisome proliferator–activated receptors are expressed in human cultured mast cells: a possible role of these receptors in negative regulation of mast cell activation. Eur. J. Immunol. 30, 3363–3370 (2000).

    Article  CAS  PubMed  Google Scholar 

  32. Torres, R.C. et al. Activation of PPARγ by restores mast cell numbers and reactivity in alloxan-diabetic rats by reducing the systemic glucocorticoid levels. Eur. J. Pharmacol. 691, 261–267 (2012).

    Article  CAS  PubMed  Google Scholar 

  33. Ahmadian, M. et al. PPARγ signaling and metabolism: the good, the bad and the future. Nat. Med. 19, 557–566 (2013).

    Article  CAS  PubMed  Google Scholar 

  34. Wakabayashi, K. et al. The peroxisome proliferator–activated receptor γ/retinoid X receptor α heterodimer targets the histone modification enzyme PR-Set7/Setd8 gene and regulates adipogenesis through a positive feedback loop. Mol. Cell. Biol. 29, 3544–3555 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Szatmari, I. et al. PPARγ regulates the function of human dendritic cells primarily by altering lipid metabolism. Blood 110, 3271–3280 (2007).

    Article  CAS  PubMed  Google Scholar 

  36. Step, S.E. et al. Anti-diabetic rosiglitazone remodels the adipocyte transcriptome by redistributing transcription to PPARγ-driven enhancers. Genes Dev. 28, 1018–1028 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Ohtake, H., Ichikawa, N., Okada, M. & Yamashita, T. Transmembrane phosphoprotein Csk-binding protein/phosphoprotein associated with glycosphingolipid-enriched microdomains as a negative feedback regulator of mast cell signaling through the FcɛRI. J. Immunol. 168, 2087–2090 (2002).

    Article  CAS  PubMed  Google Scholar 

  38. Broadfield, E.C. et al. A case–control study of dietary and erythrocyte membrane fatty acids in asthma. Clin. Exp. Allergy 34, 1232–1236 (2004).

    Article  CAS  PubMed  Google Scholar 

  39. Woods, R.K., Raven, J.M., Walters, E.H., Abramson, M.J. & Thien, F.C. Fatty acid levels and risk of asthma in young adults. Thorax 59, 105–110 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Almqvist, C. et al. Omega-3 and omega-6 fatty acid exposure from early life does not affect atopy and asthma at age 5 years. J. Allergy Clin. Immunol. 119, 1438–1444 (2007).

    Article  CAS  PubMed  Google Scholar 

  41. Chiurchiù, V. et al. Proresolving lipid mediators resolvin D1, resolvin D2, and maresin 1 are critical in modulating T cell responses. Sci. Transl. Med. 8, 353ra111 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  42. Colegio, O.R. et al. Functional polarization of tumour-associated macrophages by tumour-derived lactic acid. Nature 513, 559–563 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Miki, Y. et al. Dual roles of group IID phospholipase A2 in inflammation and cancer. J. Biol. Chem. 291, 15588–15601 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Rivera, J., Kinet, J.P., Kim, J., Pucillo, C. & Metzger, H. Studies with a monoclonal antibody to the β subunit of the receptor with high affinity for immunoglobulin E. Mol. Immunol. 25, 647–661 (1988).

    Article  CAS  PubMed  Google Scholar 

  45. Kono, N. et al. Protection against oxidative stress–induced hepatic injury by intracellular type II platelet-activating factor acetylhydrolase by metabolism of oxidized phospholipids in vivo. J. Biol. Chem. 283, 1628–1636 (2008).

    Article  CAS  PubMed  Google Scholar 

  46. Yoda, E. et al. Mitochondrial dysfunction and reduced prostaglandin synthesis in skeletal muscle of group VIB Ca2+-independent phospholipase A2γ-deficient mice. J. Lipid Res. 51, 3003–3015 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Bligh, E.G. & Dyer, W.J. A rapid method of total lipid extraction and purification. Can. J. Biochem. Physiol. 37, 911–917 (1959).

    Article  CAS  PubMed  Google Scholar 

  48. Fujisawa, D. et al. Expression of Mas-related gene X2 on mast cells is upregulated in the skin of patients with severe chronic urticaria. J. Allergy Clin. Immunol. 134, 622–633 (2014).

    Article  CAS  PubMed  Google Scholar 

  49. Lee, H. et al. Activation of human synovial mast cells from rheumatoid arthritis or osteoarthritis patients in response to aggregated IgG through Fcγ receptor I and Fcγ receptor II. Arthritis Rheum. 65, 109–119 (2013).

    Article  CAS  PubMed  Google Scholar 

Download references

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

  1. Yuta Shimanaka and Nozomu Kono: These authors contributed equally to this work.

Authors and 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

Authors
  1. Yuta Shimanaka
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Nozomu Kono
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yoshitaka Taketomi
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Makoto Arita
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Yoshimichi Okayama
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Yuki Tanaka
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Yasumasa Nishito
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Tatsuki Mochizuki
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Hiroyuki Kusuhara
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Alexander Adibekian
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Benjamin F Cravatt
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Makoto Murakami
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Hiroyuki Arai
    View author publications

    You can also search for this author in PubMed Google Scholar

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.

Corresponding authors

Correspondence to Makoto Murakami or Hiroyuki Arai.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Text, Figures and Tables

Supplementary Note, Supplementary Figures 1–7 and Supplementary Tables 1–5 (PDF 11256 kb)

Life Sciences Reporting Summary (PDF 143 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

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

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

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

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing