Monocytes, neutrophils, and platelets cooperate to initiate and propagate venous thrombosis in mice in vivo.
Monocytes, neutrophils, and platelets cooperate to initiate and propagate venous thrombosis in mice in vivo.
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DOI：
10.1084/jem.20112322
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发表时间：
2012-04-09
期刊：
影响因子：
--
通讯作者：
Massberg S
中科院分区：
文献类型：
--
作者：
von Brühl ML;Stark K;Steinhart A;Chandraratne S;Konrad I;Lorenz M;Khandoga A;Tirniceriu A;Coletti R;Köllnberger M;Byrne RA;Laitinen I;Walch A;Brill A;Pfeiler S;Manukyan D;Braun S;Lange P;Riegger J;Ware J;Eckart A;Haidari S;Rudelius M;Schulz C;Echtler K;Brinkmann V;Schwaiger M;Preissner KT;Wagner DD;Mackman N;Engelmann B;Massberg S
深静脉血栓形成是由单核细胞、中性粒细胞和血小板之间的相互作用介导的。深静脉血栓形成（DVT）是心血管死亡的主要原因。促进DVT的事件序列仍然不清楚，主要是由于缺乏适当的啮齿动物模型。我们描述了一种新的小鼠DVT模型，该模型再现了频繁的触发，并且类似于人类DVT的时间过程、组织学特征和临床表现。我们通过活体双光子和落射荧光显微镜证实血液单核细胞和中性粒细胞沿静脉内皮沿着并粘附在静脉内皮上为DVT的发展提供了起始刺激。使用条件突变体和骨髓嵌合体，我们表明，血管内激活的外源性凝血途径，通过组织因子（TF）来源于髓系白细胞引起广泛的管腔内纤维蛋白形成特征的DVT。我们证明，血栓居民中性粒细胞是必不可少的后续DVT传播的结合因子XII（FXII），并通过支持其激活通过释放中性粒细胞胞外陷阱（NET）。相应地，中性粒细胞减少症、FXII的遗传消融或NET的分解各自赋予针对DVT扩增的保护。血小板通过糖蛋白Ibα与先天性免疫细胞结合，并通过促进白细胞募集和刺激嗜中性粒细胞依赖性凝血促进DVT进展。因此，我们确定了单核细胞，中性粒细胞和血小板之间的串扰负责DVT的启动和扩增，并诱导其独特的临床特征。
Deep vein thrombosis initiation is mediated by cross talk between monocytes, neutrophils, and platelets. Deep vein thrombosis (DVT) is a major cause of cardiovascular death. The sequence of events that promote DVT remains obscure, largely as a result of the lack of an appropriate rodent model. We describe a novel mouse model of DVT which reproduces a frequent trigger and resembles the time course, histological features, and clinical presentation of DVT in humans. We demonstrate by intravital two-photon and epifluorescence microscopy that blood monocytes and neutrophils crawling along and adhering to the venous endothelium provide the initiating stimulus for DVT development. Using conditional mutants and bone marrow chimeras, we show that intravascular activation of the extrinsic pathway of coagulation via tissue factor (TF) derived from myeloid leukocytes causes the extensive intraluminal fibrin formation characteristic of DVT. We demonstrate that thrombus-resident neutrophils are indispensable for subsequent DVT propagation by binding factor XII (FXII) and by supporting its activation through the release of neutrophil extracellular traps (NETs). Correspondingly, neutropenia, genetic ablation of FXII, or disintegration of NETs each confers protection against DVT amplification. Platelets associate with innate immune cells via glycoprotein Ibα and contribute to DVT progression by promoting leukocyte recruitment and stimulating neutrophil-dependent coagulation. Hence, we identified a cross talk between monocytes, neutrophils, and platelets responsible for the initiation and amplification of DVT and for inducing its unique clinical features.
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