Interleukin‐5 drives glycolysis and reactive oxygen species‐dependent citric acid cycling by eosinophils

Introduction Eosinophils have been long implicated in antiparasite immunity and allergic diseases and, more recently, in regulating adipose tissue homeostasis. The metabolic processes that govern eosinophils, particularly upon activation, are unknown. Methods Peripheral blood eosinophils were isolat...

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Published in:Allergy (Copenhagen) 2020-06, Vol.75 (6), p.1361-1370
Main Authors: Jones, Nicholas, Vincent, Emma E., Felix, Lindsey C., Cronin, James G., Scott, Louis M., Hole, Paul S., Lacy, Paige, Thornton, Catherine A.
Format: Article
Language:English
Subjects:
1-Phosphatidylinositol 3-kinase
Adenine
Adipose tissue
AKT protein
Allergic diseases
Cell activation
Cells, Cultured
Citric Acid
Citric Acid Cycle
Cytokines
Eosinophils
Gas chromatography
Glutamine
Glycolysis
Homeostasis
Humans
IL‐5
Interleukin-3
Interleukin-5
Intermediates
Lactic acid
Leukocytes (eosinophilic)
Leukocytes (granulocytic)
Macrophages
Mass spectroscopy
Metabolic flux
Metabolism
Metabolites
Mitochondria
NAD(P)H oxidase
NADPH-diaphorase
Peripheral blood
Phosphatidylinositol 3-Kinases
Reactive Oxygen Species
TCA cycle
Tricarboxylic acid cycle
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Summary:Introduction Eosinophils have been long implicated in antiparasite immunity and allergic diseases and, more recently, in regulating adipose tissue homeostasis. The metabolic processes that govern eosinophils, particularly upon activation, are unknown. Methods Peripheral blood eosinophils were isolated for the analysis of metabolic processes using extracellular flux analysis and individual metabolites by stable isotope tracer analysis coupled to gas chromatography‐mass spectrometry following treatment with IL‐3, IL‐5 or granulocyte‐macrophage colony‐stimulating factor (GM‐CSF). Eosinophil metabolism was elucidated using pharmacological inhibitors. Results Human eosinophils engage a largely glycolytic metabolism but also employ mitochondrial metabolism. Cytokine stimulation generates citric acid cycle (TCA) intermediates from both glucose and glutamine revealing this previously unknown role for mitochondria upon eosinophil activation. We further show that the metabolic programme driven by IL‐5 is dependent on the STAT5/PI3K/Akt signalling axis and that nicotinamide adenine dinucleotide phosphate oxidase (NOX)‐dependent ROS production might be a driver of mitochondrial metabolism upon eosinophil activation. Conclusion We demonstrate for the first time that eosinophils are capable of metabolic plasticity, evidenced by increased glucose‐derived lactate production upon ROS inhibition. Collectively, this study reveals a role for both glycolysis and mitochondrial metabolism in cytokine‐stimulated eosinophils. Selective targeting of eosinophil metabolism may be of therapeutic benefit in eosinophil‐mediated diseases and regulation of tissue homeostasis. IL‐3, IL‐5 or GM‐CSF stimulated eosinophils increase glycolysis levels. Cytokine‐stimulated eosinophils depend on mitochondrial metabolism via generation of TCA cycle metabolites. Inhibition of NADPH oxidase activity drives metabolic plasticity of IL‐5 stimulated eosinophils. Abbreviations: DPI, diphenyleneiodonium; NADPH, nicotinamide adenine dinucleotide phosphate; TCA, tricarboxylic acid cycle
ISSN:0105-4538
1398-9995
DOI:10.1111/all.14158