Neutrophil Extracellular Traps Drive Endothelial-to-Mesenchymal Transition
Neutrophil Extracellular Traps Drive Endothelial-to-Mesenchymal Transition
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DOI：
10.1161/atvbaha.117.309002
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发表时间：
2017-07-01
影响因子：
8.7
通讯作者：
van der Vlag, Johan
中科院分区：
文献类型：
--
作者：
Pieterse, Elmar;Rother, Nils;van der Vlag, Johan
目的：在多种血液学和自身免疫性疾病（包括狼疮肾炎）中，中性粒细胞胞外陷阱（NETs）的过度释放和降解受损导致NETs持续暴露于内皮。本研究旨在揭示NETs危害血管完整性的机制。方法与结果：将微血管内皮细胞和大血管内皮细胞暴露于NETs，并在体外和体内测定其对内皮完整性和功能的影响。我们发现内皮细胞通过晚期糖基化终产物受体内化NETs的能力有限。内皮细胞对NETs的吞噬能力溢出导致NETs持续存在于细胞外，这迅速改变了内皮细胞-细胞接触，并通过弹性酶介导的细胞间连接蛋白VE-cadherin的蛋白水解诱导血管渗漏和跨内皮白蛋白通过。此外，net相关的弹性蛋白酶促进了连接β -连环蛋白的核易位，并诱导内皮细胞向间质转化。在体内，在MRL/lpr患病小鼠和狼疮性肾炎患者的肾脏样本中可以鉴定出NETs，在这些患者中，肾小球中NETs的存在与蛋白尿的严重程度以及肾小球内皮细胞向间质细胞的转化相关。结论-这些结果表明，过量的NETs超过内皮细胞对NETs的吞噬能力，并通过VE-cadherin的降解和随后的β -catenin信号的激活促进血管渗漏和内皮向间质转化。我们的数据表明，NET相关弹性蛋白酶是预防以NET异常释放为特征的疾病的内皮改变的潜在治疗靶点。可视化概述—本文提供了一个在线可视化概述。
Objective-An excessive release and impaired degradation of neutrophil extracellular traps (NETs) leads to the continuous exposure of NETs to the endothelium in a variety of hematologic and autoimmune disorders, including lupus nephritis. This study aims to unravel the mechanisms through which NETs jeopardize vascular integrity.Approach and Results-Microvascular and macrovascular endothelial cells were exposed to NETs, and subsequent effects on endothelial integrity and function were determined in vitro and in vivo. We found that endothelial cells have a limited capacity to internalize NETs via the receptor for advanced glycation endproducts. An overflow of the phagocytic capacity of endothelial cells for NETs resulted in the persistent extracellular presence of NETs, which rapidly altered endothelial cell-cell contacts and induced vascular leakage and transendothelial albumin passage through elastase-mediated proteolysis of the intercellular junction protein VE-cadherin. Furthermore, NET-associated elastase promoted the nuclear translocation of junctional beta-catenin and induced endothelial-to-mesenchymal transition in cultured endothelial cells. In vivo, NETs could be identified in kidney samples of diseased MRL/lpr mice and patients with lupus nephritis, in whom the glomerular presence of NETs correlated with the severity of proteinuria and with glomerular endothelial-to-mesenchymal transition.Conclusions-These results indicate that an excess of NETs exceeds the phagocytic capacity of endothelial cells for NETs and promotes vascular leakage and endothelial-to-mesenchymal transition through the degradation of VE-cadherin and the subsequent activation of beta-catenin signaling. Our data designate NET-associated elastase as a potential therapeutic target in the prevention of endothelial alterations in diseases characterized by aberrant NET release.Visual Overview-An online visual overview is available for this article.