Heme-induced neutrophil extracellular traps contribute to the pathogenesis of sickle cell disease
Heme-induced neutrophil extracellular traps contribute to the pathogenesis of sickle cell disease
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DOI：
10.1182/blood-2013-10-529982
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发表时间：
2014-06-12
期刊：
影响因子：
20.3
通讯作者：
Frenette, Paul S.
中科院分区：
文献类型：
--
作者：
Chen, Grace;Zhang, Dachuan;Frenette, Paul S.
镰状细胞病（SCD）的特征是反复发作的血管闭塞，其中中性粒细胞活化起主要作用。该疾病与慢性溶血相关，伴有无细胞血红蛋白和血红素升高。随后血红素清除蛋白的耗竭导致非特异性血红素摄取和血红素催化的活性氧的产生。在这里，我们已经确定了一个新的作用血红素诱导中性粒细胞胞外陷阱（NET）形成SCD。NET是由颗粒酶修饰的去致密染色质，并由活化的中性粒细胞释放。在人源化SCD小鼠中，我们已经检测到肺中的NET和血浆中的可溶性NET组分。NET的存在与这些小鼠的体温过低和死亡有关，这可以通过用DNase I处理拆除NET来分别预防和延迟。我们已经确定血红素作为血浆因子，刺激中性粒细胞释放NET在体外和体内。增加或降低血浆血红素浓度可以分别诱导或阻止体内NET形成，表明血红素在刺激SCD中NET释放中起着至关重要的作用。因此，我们的研究结果表明，NET显着有助于SCD的发病机制，并可以作为治疗SCD的治疗靶点。
Sickle cell disease (SCD) is characterized by recurring episodes of vascular occlusion in which neutrophil activation plays a major role. The disease is associated with chronic hemolysis with elevated cell-free hemoglobin and heme. The ensuing depletion of heme scavenger proteins leads to nonspecific heme uptake and heme-catalyzed generation of reactive oxygen species. Here, we have identified a novel role for heme in the induction of neutrophil extracellular trap (NET) formation in SCD. NETs are decondensed chromatin decorated by granular enzymes and are released by activated neutrophils. In humanized SCD mice, we have detected NETs in the lungs and soluble NET components in plasma. The presence of NETs was associated with hypothermia and death of these mice, which could be prevented and delayed, respectively, by dismantling NETs with DNase I treatment. We have identified heme as the plasma factor that stimulates neutrophils to release NETs in vitro and in vivo. Increasing or decreasing plasma heme concentrations can induce or prevent, respectively, in vivo NET formation, indicating that heme plays a crucial role in stimulating NET release in SCD. Our results thus suggest that NETs significantly contribute to SCD pathogenesis and can serve as a therapeutic target for treating SCD.