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首页> 外文期刊>Allergy >Interleukin‐5 drives glycolysis and reactive oxygen species‐dependent citric acid cycling by eosinophils
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Interleukin‐5 drives glycolysis and reactive oxygen species‐dependent citric acid cycling by eosinophils

机译：白细胞介素-5驱动糖酵解和反应性氧物种依赖性柠檬酸循环嗜酸性粒细胞

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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.
机译：摘要嗜酸性粒细胞长期涉及抗哌酸盐免疫和过敏性疾病，最近在调节脂肪组织稳态中。治理嗜酸性粒细胞，特别是在激活时的代谢过程是未知的。方法将外周血嗜酸性粒细胞分析使用细胞外通量分析和单位代谢物通过稳定同位素示踪分析分析代谢物分析，与IL-3，IL-5或粒细胞 - 巨噬细胞凝聚因子处理后加入气相色谱 - 质谱分析（ GM-CSF）。使用药理学抑制剂阐明了嗜酸性粒细胞代谢。结果人嗜酸性粒细胞吸引了大部分糖酵解代谢，但也雇用了线粒体代谢。细胞因子刺激产生葡萄糖和谷氨酰胺的柠檬酸循环（TCA）中间体，揭示了对嗜酸性粒细胞激活后线粒体的这种先前未知的作用。我们进一步表明，由IL-5驱动的代谢程序依赖于Stat5 / Pi3k / akt信号轴，并且烟酰胺腺嘌呤二核苷酸磷酸氧化酶（NOx） - 依赖性ROS产生可能是嗜酸性粒细胞激活对线粒体代谢的驱动力。结论我们首次证明了嗜酸性粒细胞能够代谢可塑性，通过增加葡萄糖衍生的乳酸乳酸盐产生的抑制作用。本研究统一地揭示了糖醇分解和线粒体代谢在细胞因子刺激的嗜酸性粒细胞中的作用。选择性靶向嗜酸性粒细胞代谢可能是嗜酸性粒细胞介导的疾病和组织稳态调控中的治疗益处。

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