Erythrocyte adaptive metabolic reprogramming under physiological and pathological hypoxia.
Erythrocyte adaptive metabolic reprogramming under physiological and pathological hypoxia.
复制标题
在生理和病理缺氧下，红细胞自适应代谢重编程。
DOI：
10.1097/moh.0000000000000574
复制
发表时间：
2020-05
影响因子：
3.2
通讯作者：
Xia Y
中科院分区：
文献类型：
--
作者：
D'Alessandro A;Xia Y
红细胞是我们身体中最丰富的细胞类型，作为氧气（O2）的载体/递送者和传感器。红细胞O2输送能力由复杂的代谢控制精细调节。近年来，公正和稳健的人类代谢组学筛选和小鼠遗传研究推进了红细胞研究，揭示了红细胞缺氧代谢重编程在高海拔正常个体和缺氧患者（如镰状细胞病（SCD）和慢性肾病（CKD））中的不同作用。在这里，我们总结了最近的进展，并强调潜在的治疗可能性。最初的研究表明，可溶性CD 73（sCD 73，将AMP转化为腺苷）升高导致循环腺苷增加，从而激活A2 B腺苷受体（ADORA 2B）。通过该轴的信号传导通过红细胞特异性合成鞘氨醇-1-磷酸（S1 P）协同加强。最终，这些机制促进了2，3-二磷酸甘油酸（2，3-BPG）的产生，2，3-BPG是一种红细胞特异性变构调节剂，其降低血红蛋白-O2结合亲和力，从而诱导SCD中的脱氧镰状Hb（deoxyHbS）、deoxyHbS聚合、镰状化、慢性炎症和组织损伤。与SCD相似，人类上升到高海拔时血浆腺苷和红细胞S1 P升高。在高海拔条件下，这两种代谢产物有利于诱导红细胞代谢重编程和2，3-BPG的合成，从而增加O2的释放，以对抗缺氧组织损伤。后续研究表明，红细胞平衡型核苷转运蛋白1（eENT 1）是一种关键的嘌呤能细胞成分，控制高海拔地区的人类和缺氧条件下的小鼠的血浆腺苷，并强调了更快和更高的血浆腺苷上升后，由于先前缺氧诱导的eENT 1降解。最近的研究证明了红细胞ADORA 2B介导的2，3-BPG产生在CKD中的有益作用。综上所述，这些发现揭示了红细胞缺氧代谢重编程在高海拔地区正常人和CKD患者与SCD患者中的不同作用，并立即提出了在这些群体中对抗缺氧的差异和精确治疗。
The erythrocyte is the most abundant cell type in our body, acting as both a carrier/deliverer and sensor of oxygen (O2). Erythrocyte O2 delivery capacity is finely regulated by sophisticated metabolic control. In recent years, unbiased and robust human metabolomics screening and mouse genetic studies have advanced erythroid research revealing the differential role of erythrocyte hypoxic metabolic reprogramming in normal individuals at high altitudes and patients facing hypoxia, such as sickle cell disease (SCD) and chronic kidney disease (CKD). Here we summarize recent progress and highlight potential therapeutic possibilities. Initial studies showed that elevated soluble CD73 (sCD73, converts AMP to adenosine) results in increased circulating adenosine that activates the A2B adenosine receptor (ADORA2B). Signaling through this axis is co-operatively strengthened by erythrocyte-specific synthesis of sphingosine-1-phosphate (S1P). Ultimately, these mechanisms promote the generation of 2,3-bisphosphoglycerate (2,3-BPG), an erythrocyte specific allosteric modulator that decreases hemoglobin-O2 binding affinity and thus induces deoxygenated sickle Hb (deoxyHbS), deoxyHbS polymerization, sickling, chronic inflammation and tissue damage in SCD. Similar to SCD, plasma adenosine and erythrocyte S1P are elevated in humans ascending to high altitude. At high altitude these two metabolites are beneficial to induce erythrocyte metabolic reprogramming and the synthesis of 2,3-BPG and thus increase O2 delivery to counteract hypoxic tissue damage. Follow up studies showed that erythrocyte equilibrative nucleoside transporter 1 (eENT1) is a key purinergic cellular component controlling plasma adenosine in humans at high altitude and mice under hypoxia and underlies the quicker and higher elevation of plasma adenosine upon re-ascent due to prior hypoxia-induced degradation of eENT1. More recent studies demonstrated the beneficial role of erythrocyte ADORA2B-mediated 2,3-BPG production in CKD. aken together, these findings revealed the differential role of erythrocyte hypoxic metabolic reprogramming in normal humans at high altitude and patients with CKD vs SCD patients and immediately suggest differential and precision therapies to counteract hypoxia among these groups.