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

Jun Miyata; Koichi Fukunaga; Yusuke Kawashima; Takashi Watanabe; Akina Saitoh; Tomomi Hirosaki; Yasutomo Araki; Toru Kikawada; Tomoko Betsuyaku; Osamu Ohara; Makoto Arita

doi:10.1111/all.13726

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

Jun Miyata, Koichi Fukunaga, Yusuke Kawashima, Takashi Watanabe, Akina Saitoh, Tomomi Hirosaki, Yasutomo Araki, Toru Kikawada, Tomoko Betsuyaku, Osamu Ohara, Makoto Arita

Research output: Contribution to journal › Article › peer-review

44 Citations (Scopus)

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.

Original language	English
Pages (from-to)	1113-1124
Number of pages	12
Journal	Allergy: European Journal of Allergy and Clinical Immunology
Volume	74
Issue number	6
DOIs	https://doi.org/10.1111/all.13726
Publication status	Published - 2019 Jun

Keywords

GGT5
chronic rhinosinusitis
human eosinophil
lipid mediator
multi-omics

ASJC Scopus subject areas

Immunology and Allergy
Immunology

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10.1111/all.13726

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Miyata, J., Fukunaga, K., Kawashima, Y., Watanabe, T., Saitoh, A., Hirosaki, T., Araki, Y., Kikawada, T., Betsuyaku, T., Ohara, O., & Arita, M. (2019). Dysregulated fatty acid metabolism in nasal polyp-derived eosinophils from patients with chronic rhinosinusitis. Allergy: European Journal of Allergy and Clinical Immunology, 74(6), 1113-1124. https://doi.org/10.1111/all.13726

Miyata, J , Fukunaga, K, Kawashima, Y, Watanabe, T, Saitoh, A, Hirosaki, T, Araki, Y, Kikawada, T, Betsuyaku, T, Ohara, O & Arita, M 2019, 'Dysregulated fatty acid metabolism in nasal polyp-derived eosinophils from patients with chronic rhinosinusitis', Allergy: European Journal of Allergy and Clinical Immunology, vol. 74, no. 6, pp. 1113-1124. https://doi.org/10.1111/all.13726

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title = "Dysregulated fatty acid metabolism in nasal polyp-derived eosinophils from patients with chronic rhinosinusitis",

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 CD69hi CCR3low CXCR4- siglec-8int 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.",

keywords = "GGT5, chronic rhinosinusitis, human eosinophil, lipid mediator, multi-omics",

author = "Jun Miyata and Koichi Fukunaga and Yusuke Kawashima and Takashi Watanabe and Akina Saitoh and Tomomi Hirosaki and Yasutomo Araki and Toru Kikawada and Tomoko Betsuyaku and Osamu Ohara and Makoto Arita",

note = "Funding Information: 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. We thank Koichiro Asano (Tokai University) and Yosuke Isobe (RIKEN-IMS) for advice and critical input regarding this study, and Mie Honda, Kanako Igarashi and Kazutaka Ikeda (RIKEN-IMS) for technical assistance of LC-MS–based lipidomics. 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. Publisher Copyright: {\textcopyright} 2019 EAACI and John Wiley and Sons A/S. Published by John Wiley and Sons Ltd.",

year = "2019",

month = jun,

doi = "10.1111/all.13726",

language = "English",

volume = "74",

pages = "1113--1124",

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number = "6",

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T1 - Dysregulated fatty acid metabolism in nasal polyp-derived eosinophils from patients with chronic rhinosinusitis

AU - Miyata, Jun

AU - Fukunaga, Koichi

AU - Kawashima, Yusuke

AU - Watanabe, Takashi

AU - Saitoh, Akina

AU - Hirosaki, Tomomi

AU - Araki, Yasutomo

AU - Kikawada, Toru

AU - Betsuyaku, Tomoko

AU - Ohara, Osamu

AU - Arita, Makoto

N1 - Funding Information: 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. We thank Koichiro Asano (Tokai University) and Yosuke Isobe (RIKEN-IMS) for advice and critical input regarding this study, and Mie Honda, Kanako Igarashi and Kazutaka Ikeda (RIKEN-IMS) for technical assistance of LC-MS–based lipidomics. 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. Publisher Copyright: © 2019 EAACI and John Wiley and Sons A/S. Published by John Wiley and Sons Ltd.

PY - 2019/6

Y1 - 2019/6

N2 - 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 CD69hi CCR3low CXCR4- siglec-8int 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.

AB - 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 CD69hi CCR3low CXCR4- siglec-8int 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.

KW - GGT5

KW - chronic rhinosinusitis

KW - human eosinophil

KW - lipid mediator

KW - multi-omics

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ER -

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

Abstract

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