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

Abstract

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. K E Y W O R D Seosinophils, glycolysis, IL-5, metabolism, TCA cycle

Heterogeneity of Intestinal Tissue Eosinophils: Potential Considerations for Next-Generation Eosinophil-Targeting Strategies

“…In addition to phenotypic diversity, spatial redistributions of intestinal eosinophils (even in the absence of increased recruitment) also accompany disease settings; for example, allergen ingestion elicits redistribution of small intestinal eosinophils into villus LP [67], and in IBD (but not control) patients, actively degranulating eosinophils associate with cholinergic fibers [68]. Eosinophils also display significant metabolic flexibility [69,70], and further studies are needed to investigate contributions of metabolic plasticity to eosinophil functional sub-phenotypes.…”

Adipose Tissue Immunomodulation: A Novel Therapeutic Approach in Cardiovascular and Metabolic Diseases

“…Nevertheless, enhancing AT eosinophil abundance is debated since several studies demonstrated no beneficial or even negative outcomes of this approach (220). Required for the production of ROS LPS-treated mouse bone marrow-derived neutrophils treated with Antimycin A or myxothiazol (190) Required for migration Polg CRISPR/Cas9-mediated neutrophil-specific knockout in Zebra fish (191) Pentose phosphate pathway ⇑ Required for NETosis Amyloid fibril-and phorbol myristate acetate-stimulated human neutrophils (192) Required for ROS generation and NETosis G6PD-deficient patients G6PD-deficient mice (193,194) TCA cycle ⇑ Required for chemotaxis Isocitrate dehydrogenase 1 mutant mice (195) Required for differentiation Mouse Atg5-deficient neutrophils and an in vitro model of differentiating neutrophils (196) Lipogenesis ⇑ Required for differentiation Atg7-deficient neutrophil precursors (197) Required for neutrophil maintanence FASlox/lox-Rosa26-CreER mice (198) Glutamine metabolism It was suggested that circulating eosinophils display a greater metabolic flexibility in comparison to neutrophils (200,201). Further investigation into the metabolic rewiring of eosinophils (shown in Table 3) is required as emerging roles of eosinophils suggest a central modulatory function in AT homeostasis.…”

Dysregulation of Pyruvate Kinase M2 Promotes Inflammation in a Mouse Model of Obese Allergic Asthma

“…Attenuated lactate production in the BAL fluid and lung tissue in obese versus lean allergic mice may be the result of reduced T-cell activation in obese mice. Eosinophils also rely on glycolytic metabolism as a source of energy (39,40), and high-fat diet feeding was shown to reduce eosinophil recruitment to the lung after ovalbumin challenge (41). The trending decrease in eosinophils in the BAL fluid of obese compared with lean allergic mice could also explain the observed decrease in lactate production.…”