Jun Miyata1,2,3, Koichi Fukunaga3, Yusuke Kawashima4, Takashi Watanabe4, Akina Saitoh5, Tomomi Hirosaki6, Yasutomo Araki7, Toru Kikawada7, Tomoko Betsuyaku3, Osamu Ohara4, Makoto Arita1,2,8. 1. Laboratory for Metabolomics, RIKEN Center for Integrative Medical Sciences, Kanagawa, Japan. 2. Graduate School of Medical Life Science, Yokohama City University, Kanagawa, Japan. 3. Division of Pulmonary Medicine, Department of Medicine, Keio University School of Medicine, Tokyo, Japan. 4. Laboratory for Integrative Genomics, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan. 5. Tsukuba Research Institute, Ono Pharmaceutical Co., Ltd., Tsukuba, Japan. 6. Minase Research Institute, Ono Pharmaceutical Co., Ltd., Osaka, Japan. 7. Nose Clinic Tokyo, Tokyo, Japan. 8. Division of Physiological Chemistry and Metabolism, Faculty of Pharmacy, Keio University, Tokyo, Japan.
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.
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.
Authors: Atsushi Kato; Anju T Peters; Whitney W Stevens; Robert P Schleimer; Bruce K Tan; Robert C Kern Journal: Allergy Date: 2021-09-15 Impact factor: 14.710