Metabolic Reprogramming Mediates Delayed Apoptosis of Human Neutrophils Infected With Francisella tularensis.
Metabolic Reprogramming Mediates Delayed Apoptosis of Human Neutrophils Infected With Francisella tularensis.
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DOI：
10.3389/fimmu.2022.836754
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发表时间：
2022
影响因子：
7.3
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中科院分区：
文献类型：
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中性粒细胞（多形核白细胞，PMNs）具有明显的短寿命，细胞存活和死亡的严格调节对其正常功能至关重要。我们以前证明，土拉热弗朗西丝菌延长人类中性粒细胞的寿命，这elevening一个受损的免疫反应的特点是中性粒细胞功能障碍。在此，我们扩展了这些研究，包括我们的转录谱数据，并采用海马细胞外通量分析，气相色谱-质谱代谢物分析，流式细胞术和其他几种生化方法来证明在F.土拉菌感染的嗜中性粒细胞部分通过代谢重编程介导。具体地说，我们表明，F。土拉菌感染的嗜中性粒细胞表现出独特的代谢特征，其特征在于增加的糖酵解、糖酵解通量和葡萄糖摄取、戊糖磷酸途径的下调和复杂的糖原动力学。葡萄糖摄取和糖酵解是必不可少的细胞寿命，虽然葡萄糖-6-磷酸转运到内质网不是，我们确定消耗糖原作为一个潜在的触发细胞凋亡发作。与此相一致，我们还证明，在没有感染的情况下，用泛半胱天冬酶抑制剂Q-VD-OPh消融细胞凋亡足以显著增加糖酵解和糖原储存。总之，我们的数据大大推进了对中性粒细胞免疫代谢及其调节细胞寿命能力的理解。
Neutrophils (polymorphonuclear leukocytes, PMNs) have a distinctively short lifespan, and tight regulation of cell survival and death is imperative for their normal function. We demonstrated previously that Francisella tularensis extends human neutrophil lifespan, which elicits an impaired immune response characterized by neutrophil dysfunction. Herein, we extended these studies, including our transcriptional profiling data, and employed Seahorse extracellular flux analysis, gas chromatography-mass spectrometry metabolite analysis, flow cytometry and several other biochemical approaches to demonstrate that the delayed apoptosis observed in F. tularensis-infected neutrophils is mediated, in part, by metabolic reprogramming. Specifically, we show that F. tularensis-infected neutrophils exhibited a unique metabolic signature characterized by increased glycolysis, glycolytic flux and glucose uptake, downregulation of the pentose phosphate pathway, and complex glycogen dynamics. Glucose uptake and glycolysis were essential for cell longevity, although glucose-6-phosphate translocation into the endoplasmic reticulum was not, and we identify depletion of glycogen as a potential trigger of apoptosis onset. In keeping with this, we also demonstrate that ablation of apoptosis with the pan-caspase inhibitor Q-VD-OPh was sufficient to profoundly increase glycolysis and glycogen stores in the absence of infection. Taken together, our data significantly advance understanding of neutrophil immunometabolism and its capacity to regulate cell lifespan.