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

INTRODUCTION: Eosinophils have been long implicated in anti-parasite 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 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 program 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.