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Mast cell maturation is driven via a group III phospholipase A2-prostaglandin D2–DP1 receptor paracrine axis

Nature Immunology volume 14, pages 554–563 (2013)Cite this article

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Abstract

Microenvironment-based alterations in phenotypes of mast cells influence the susceptibility to anaphylaxis, yet the mechanisms underlying proper maturation of mast cells toward an anaphylaxis-sensitive phenotype are incompletely understood. Here we report that PLA2G3, a mammalian homolog of anaphylactic bee venom phospholipase A2, regulates this process. PLA2G3 secreted from mast cells is coupled with fibroblastic lipocalin-type PGD2 synthase (L-PGDS) to provide PGD2, which facilitates mast-cell maturation via PGD2 receptor DP1. Mice lacking PLA2G3, L-PGDS or DP1, mast cell–deficient mice reconstituted with PLA2G3-null or DP1-null mast cells, or mast cells cultured with L-PGDS–ablated fibroblasts exhibited impaired maturation and anaphylaxis of mast cells. Thus, we describe a lipid-driven PLA2G3–L-PGDS–DP1 loop that drives mast cell maturation.

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Figure 1: PLA2G3 is expressed in mast cells and has the ability to induce degranulation.
Figure 2: Altered anaphylaxis in mice with deletion or overexpression of PLA2G3.
Figure 3: Immature properties of tissue mast cells in Pla2g3-deficient mice.
Figure 4: Defective fibroblast-driven maturation of Pla2g3−/− BMMCs.
Figure 5: Defective mast-cell maturation and anaphylaxis by DP1 deficiency.
Figure 6: Defective mast-cell maturation and anaphylaxis by L-PGDS deficiency.
Figure 7: The PLA2G3–L-PGDS–DP1 axis facilitates maturation of human mast cells.

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Acknowledgements

We thank Y. Tanoue, H. Ohkubo, K. Araki and K. Yamamura for generating Ptges2−/− mice. This work was supported by grants-in-aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan (22116005 and 24390021 to M.M. and 23790119 and 24117724 to Y.T.), Promoting Individual Research to Nurture the Seeds of Future Innovation and Organizing Unique Innovative Network (PRESTO) of Japan Science and Technology Agency (to M.M.), and the Uehara, Mitsubishi, Terumo, Mochida and Toray Science Foundations (to M.M.).

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Authors and Affiliations

  1. Lipid Metabolism Project, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan

    Yoshitaka Taketomi, Noriko Ueno, Takumi Kojima, Hiroyasu Sato, Remi Murase, Kei Yamamoto & Makoto Murakami

  2. School of Pharmacy, Showa University, Tokyo, Japan

    Yoshitaka Taketomi, Hiroyasu Sato, Remi Murase, Momoko Kawana & Shuntaro Hara

  3. Department of Immunobiology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan

    Satoshi Tanaka

  4. School of Pharmacy and Pharmaceutical Sciences, Mukogawa Women's University, Hyogo, Japan

    Mariko Sakanaka

  5. School of Dentistry, Showa University, Tokyo, Japan

    Masanori Nakamura

  6. Core Technology and Research Center, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan

    Yasumasa Nishito

  7. Department of Dermatology, Chiba University Graduate School of Medicine, Chiba, Japan

    Naotomo Kambe

  8. Institute for Advanced Biosciences, Keio University, Yamagata, Japan

    Kazutaka Ikeda

  9. College of Life and Health Sciences, Chubu University, Aichi, Japan

    Ryo Taguchi

  10. Department of Dermatology, Kyoto University Graduate School of Medicine, Kyoto, Japan

    Satoshi Nakamizo & Kenji Kabashima

  11. Departments of Chemistry and Biochemistry, University of Washington, Washington, USA

    Michael H Gelb

  12. Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan

    Makoto Arita

  13. Department of Biochemistry, Juntendo University School of Medicine, Tokyo, Japan

    Takehiko Yokomizo

  14. Faculty of Medicine, The University of Tokyo, Tokyo, Japan

    Motonao Nakamura & Takao Shimizu

  15. Department of Nutrition, Koshien University, Hyogo, Japan

    Kikuko Watanabe

  16. Department of Advanced Medicine and Development, Bio Medical Laboratories, Saitama, Japan

    Hiroyuki Hirai

  17. Human Gene Sciences Center, Tokyo Medical and Dental University, Tokyo, Japan

    Masataka Nakamura

  18. Division of Molecular Cell Immunology and Allergology, Advanced Medical Research Center, Nihon University Graduate School of Medical Science, Tokyo, Japan

    Yoshimichi Okayama & Chisei Ra

  19. Department of Molecular Bihavioral Biology, Osaka Bioscience Institute, Osaka, Japan

    Kosuke Aritake & Yoshihiro Urade

  20. Department of Pharmaceutical Biochemistry, Graduate School of Medicine and Pharmaceutical Sciences, Kumamoto University, Kumamoto, Japan

    Kazushi Morimoto & Yukihiko Sugimoto

  21. Department of Pharmacology, Kyoto University Graduate School of Medicine, Kyoto, Japan

    Shuh Narumiya

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Contributions

Y.T. performed experiments and together with M.M. conceived and designed the study, interpreted the findings and wrote the manuscript; N.U., T.K., M.K., R.M. and H.S. performed experiments; S.T., M.S., Masanori Nakamura, Y.N., K.I., K.M., Satoshi Nakamizo, K.K., Y.O. and C.R. helped perform some experiments; K.Y., N.K., R.T., M.H.G. M.A., T.Y., Masataka Nakamura, K.W., H.H., Motonao Nakamura, K.A., Y.U., Y.S., T.S., Shu Narumiya and S.H. contributed to experimental designs.

Corresponding author

Correspondence to Makoto Murakami.

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Taketomi, Y., Ueno, N., Kojima, T. 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). https://doi.org/10.1038/ni.2586

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