Volume 74, Issue 6 pp. 1113-1124

ORIGINAL ARTICLE

Dysregulated fatty acid metabolism in nasal polyp-derived eosinophils from patients with chronic rhinosinusitis

Jun Miyata,

Jun Miyata

Laboratory for Metabolomics, RIKEN Center for Integrative Medical Sciences, Kanagawa, Japan

Graduate School of Medical Life Science, Yokohama City University, Kanagawa, Japan

Division of Pulmonary Medicine, Department of Medicine, Keio University School of Medicine, Tokyo, Japan

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Koichi Fukunaga,

Koichi Fukunaga

Division of Pulmonary Medicine, Department of Medicine, Keio University School of Medicine, Tokyo, Japan

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Yusuke Kawashima,

Yusuke Kawashima

Laboratory for Integrative Genomics, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan

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Takashi Watanabe,

Takashi Watanabe

Laboratory for Integrative Genomics, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan

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Akina Saitoh,

Akina Saitoh

Tsukuba Research Institute, Ono Pharmaceutical Co., Ltd., Tsukuba, Japan

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Tomomi Hirosaki,

Tomomi Hirosaki

Minase Research Institute, Ono Pharmaceutical Co., Ltd., Osaka, Japan

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Yasutomo Araki,

Yasutomo Araki

Nose Clinic Tokyo, Tokyo, Japan

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Toru Kikawada,

Toru Kikawada

Nose Clinic Tokyo, Tokyo, Japan

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Tomoko Betsuyaku,

Tomoko Betsuyaku

Division of Pulmonary Medicine, Department of Medicine, Keio University School of Medicine, Tokyo, Japan

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Osamu Ohara,

Osamu Ohara

Laboratory for Integrative Genomics, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan

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Makoto Arita,

Corresponding Author

Makoto Arita

[email protected]

orcid.org/0000-0001-9902-0463

Laboratory for Metabolomics, RIKEN Center for Integrative Medical Sciences, Kanagawa, Japan

Graduate School of Medical Life Science, Yokohama City University, Kanagawa, Japan

Division of Physiological Chemistry and Metabolism, Faculty of Pharmacy, Keio University, Tokyo, Japan

Correspondence

Makoto Arita, Laboratory for Metabolomics, RIKEN Center for Integrative Medical Sciences, Kanagawa, Japan.

Email: [email protected]

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Jun Miyata,

Jun Miyata

Laboratory for Metabolomics, RIKEN Center for Integrative Medical Sciences, Kanagawa, Japan

Graduate School of Medical Life Science, Yokohama City University, Kanagawa, Japan

Division of Pulmonary Medicine, Department of Medicine, Keio University School of Medicine, Tokyo, Japan

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Koichi Fukunaga,

Koichi Fukunaga

Division of Pulmonary Medicine, Department of Medicine, Keio University School of Medicine, Tokyo, Japan

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Yusuke Kawashima,

Yusuke Kawashima

Laboratory for Integrative Genomics, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan

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Takashi Watanabe,

Takashi Watanabe

Laboratory for Integrative Genomics, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan

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Akina Saitoh,

Akina Saitoh

Tsukuba Research Institute, Ono Pharmaceutical Co., Ltd., Tsukuba, Japan

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Tomomi Hirosaki,

Tomomi Hirosaki

Minase Research Institute, Ono Pharmaceutical Co., Ltd., Osaka, Japan

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Yasutomo Araki,

Yasutomo Araki

Nose Clinic Tokyo, Tokyo, Japan

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Toru Kikawada,

Toru Kikawada

Nose Clinic Tokyo, Tokyo, Japan

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Tomoko Betsuyaku,

Tomoko Betsuyaku

Division of Pulmonary Medicine, Department of Medicine, Keio University School of Medicine, Tokyo, Japan

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Osamu Ohara,

Osamu Ohara

Laboratory for Integrative Genomics, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan

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Makoto Arita,

Corresponding Author

Makoto Arita

[email protected]

orcid.org/0000-0001-9902-0463

Laboratory for Metabolomics, RIKEN Center for Integrative Medical Sciences, Kanagawa, Japan

Graduate School of Medical Life Science, Yokohama City University, Kanagawa, Japan

Division of Physiological Chemistry and Metabolism, Faculty of Pharmacy, Keio University, Tokyo, Japan

Correspondence

Makoto Arita, Laboratory for Metabolomics, RIKEN Center for Integrative Medical Sciences, Kanagawa, Japan.

Email: [email protected]

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First published: 22 January 2019

https://doi.org/10.1111/all.13726

Citations: 69

Funding information

This work was supported in part by RIKEN Special Postdoctoral Researchers Program (to J.M.), Japan Society for the Promotion of Science KAKENHI JP15H05897, 15H05898, 15H04648 (to M.A.), JP26461197 (to K.F.), Japan Science and Technology Agency Precursory Research for Embryonic Science and Technology (PRESTO) (to M.A.), and Ono Pharmaceutical Company.

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Abstract

Background

Eosinophils are multifunctional granulocytes capable of releasing various cytokines, chemokines, and lipid mediators. We previously reported dysregulated fatty acid metabolism in peripheral blood-derived eosinophils from patients with severe asthma. However, functional characteristics of eosinophils present in allergic inflammatory tissues remain largely uncharacterized.

Methods

We established a method for isolating CD69^hi CCR3^low CXCR4^- siglec-8^int eosinophils from nasal polyps of patients with eosinophilic rhinosinusitis (NP-EOS). Multi-omics analysis including lipidomics, proteomics, and transcriptomics was performed to analyze NP-EOS as compared to peripheral blood-derived eosinophils from healthy subjects (PB-EOS).

Results

Lipidomic analysis revealed impaired synthesis of prostaglandins and 15-lipoxygenase (15-LOX)-derived mediators, and selective upregulation of leukotriene D₄ production. Furthermore, proteomics and transcriptomics revealed changes in the expression of specific enzymes (GGT5, DPEP2, and 15-LOX) responsible for dysregulated lipid metabolism. Ingenuity pathway analysis indicated the importance of type 2 cytokines and pattern recognition receptor pathways. Stimulation of PB-EOS with eosinophil activators IL-5, GM-CSF, and agonists of TLR2 and NOD2 mimicked the observed changes in lipid metabolism.

Conclusion

Inflammatory tissue-derived eosinophils possess a specific phenotype with dysregulated fatty acid metabolism that may be targeted therapeutically to control eosinophilic inflammatory diseases.

Graphical Abstract

Eosinophils isolated from nasal polyps of patients with eosinophilic rhinosinusitis possess dysregulated fatty acid metabolism. Of the CysLT (cysteinyl leukotriene) biosynthetic pathway metabolites, LTD₄ production is selectively enhanced with increased expression of GGT5 (gamma-glutamyl trasferase-5) and decreased expression of DPEP2 (dipeptidase-2). Type 2 cytokines (IL-5 and GM-CSF) and agonists of TLR2 and NOD2 induce similar changes of fatty acid metabolism.

COX: Cyclooxygenase; CRS: Chronic rhinosinusitis; DPEP2: Dipeptidase-2; GGT5: Gamma-glutamyl trasferase-5; GM-CSF: Granulocyte-macrophage colony-stimulating factor; ILC2: Type 2 innate lymphoid cells; LTC4: Leukotriene C4; LTD4: Leukotriene D4; LTE4: Leukotriene E4; LXA4: Lipoxin A4; NOD2: Nucleotide binding oligomerization domain containing 2; PGE2: Prostaglandin E2; Th2: Type 2 helper T cells; TLR2: Toll-like receptor 2

CONFLICTS OF INTEREST

The authors declare that they have no conflicts of interest.

Supporting Information

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Citing Literature

Volume74, Issue6

June 2019

Pages 1113-1124

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