Metabolic Adaptation of Neutrophils in Cystic Fibrosis Airways Involves Distinct Shifts in Nutrient Transporter Expression
Metabolic Adaptation of Neutrophils in Cystic Fibrosis Airways Involves Distinct Shifts in Nutrient Transporter Expression
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DOI：
10.4049/jimmunol.1201755
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发表时间：
2013-06-15
影响因子：
4.4
通讯作者：
Tirouvanziam, Rabindra
中科院分区：
文献类型：
--
作者：
Laval, Julie;Touhami, Jawida;Tirouvanziam, Rabindra
炎症条件可以深刻改变人的中性粒细胞，这是一种通常被视为终末分化和分解代谢的白细胞亚群。在囊性纤维化(CF)患者中，中性粒细胞被招募到囊性纤维化的呼吸道中，表现出活跃的胞吐和持续的生存代谢途径的磷酸化。由于CF气道腔也以高水平的游离葡萄糖和氨基酸为特征，我们使用特定的逆转录病毒包膜衍生配体比较了Glut1(葡萄糖)和ASCT2(中性氨基酸)转运体以及PiT1和PiT2(无机磷转运体)在血液和气道中性粒细胞中的表面表达。与健康对照组相比，CF患者血液中性粒细胞上的营养转运体表达和葡萄糖摄取均无改变。然而，值得注意的是，与血液中的中性粒细胞相比，CF患者的中性粒细胞具有更高的PiT1和Glut1水平，并增加了葡萄糖摄取。根据原始颗粒吐出和散射特征，中性粒细胞可分为两个亚群，其中一个亚群表现为Glut1、ASCT2、PiT1和PiT2的表达显著增加。此外，血液中性粒细胞的体外胞吐分析表明，表面营养转运体的表达与原发(或继发)颗粒胞吐并不直接相关。虽然CF血或中性粒细胞上的营养转运蛋白的表达不受基因、年龄、性别或铜绿假单胞菌感染的影响，但口服类固醇治疗降低了中性粒细胞中Glut1和PiT2的水平。因此，从血液中招募的中性粒细胞进入CF气道腔，表现出细胞表面营养转运体的表达和葡萄糖摄取的增强，这与代谢适应一致。
Inflammatory conditions can profoundly alter human neutrophils, a leukocyte subset generally viewed as terminally differentiated and catabolic. In cystic fibrosis (CF) patients, neutrophils recruited to CF airways show active exocytosis and sustained phosphorylation of prosurvival, metabolic pathways. Because the CF airway lumen is also characterized by high levels of free glucose and amino acids, we compared surface expression of Glut1 (glucose) and ASCT2 (neutral amino acids) transporters, as well as that of PiT1 and PiT2 (inorganic phosphate transporters), in blood and airway neutrophils, using specific retroviral envelope-derived ligands. Neither nutrient transporter expression nor glucose uptake was altered on blood neutrophils from CF patients compared with healthy controls. Notably, however, airway neutrophils of CF patients had higher levels of PiT1 and Glut1 and increased glucose uptake compared with their blood counterparts. Based on primary granule exocytosis and scatter profiles, CF airway neutrophils could be divided into two subsets, with one of the subsets characterized by more salient increases in Glut1, ASCT2, PiT1, and PiT2 expression. Moreover, in vitro exocytosis assays of blood neutrophils suggest that surface nutrient transporter expression is not directly associated with primary (or secondary) granule exocytosis. Although expression of nutrient transporters on CF blood or airway neutrophils was not altered by genotype, age, gender, or Pseudomonas aeruginosa infection, oral steroid treatment decreased Glut1 and PiT2 levels in blood neutrophils. Thus, neutrophils recruited from blood into the CF airway lumen display augmented cell surface nutrient transporter expression and glucose uptake, consistent with metabolic adaptation.