Natural killer cells induce neutrophil extracellular trap formation in venous thrombosis
Natural killer cells induce neutrophil extracellular trap formation in venous thrombosis
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DOI：
10.1111/jth.14339
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发表时间：
2019-02-01
影响因子：
10.4
通讯作者：
Blostein, M. D.
中科院分区：
文献类型：
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作者：
Bertin, F. -R.;Rys, R. N.;Blostein, M. D.
背景中性粒细胞通过释放中性粒细胞胞外陷阱（NETs）促进静脉血栓形成，但其形成机制尚不清楚。体外数据显示干扰素（IFN）-γ诱导NET的形成。目的探讨IFN-γ和T细胞表达的转录因子T-box（Tbet）是否通过激活中性粒细胞促进静脉血栓形成。方法在IFN-γ（-/-）、Tbet（-/-）和野生型（WT）小鼠的下腔静脉中通过限流诱导静脉血栓形成。48小时后，使用高频超声测量血栓大小。NET形成通过免疫荧光测定。结果和结论Tbet（-/-）和IFN-γ（-/-）小鼠的血栓形成减少，表明Tbet/IFN-γ表达细胞是静脉血栓形成所必需的。血栓形成期间形成的NET数量在Tbet（-/-）和IFN-γ（-/-）小鼠中显著较低。在用IFN-γ阻断抗体处理的WT小鼠中，NET形成也减少。将重组IFN-γ注射到IFN-γ（-/-）小鼠中挽救了表型。在静脉血栓形成诱导之前，自然杀伤（NK）细胞被特异性耗尽。NK细胞耗竭导致NET形成减少和血栓变小，表明NK细胞是血栓形成所需的。在耗竭小鼠中，WT NK细胞的过继转移诱导了与WT小鼠相似的血栓形成负荷。相比之下，IFN-γ（-/-）NK细胞的过继转移导致血栓大小与耗竭小鼠相似。在体外，我们发现WT中性粒细胞与IFN-γ（-/-）NK细胞共培养时释放较少的NET。这项研究表明，NK细胞依赖性IFN-γ的产生是至关重要的血栓发展，促进中性粒细胞的NET的形成。
Background Neutrophils contribute to venous thrombosis through the release of neutrophil extracellular traps (NETs), but the mechanism triggering their formation remains unclear. In vitro data show that interferon (IFN)-gamma induces the formation of NETs. Objectives To determine whether IFN-gamma and the transcription factor T-box expressed on T cells (Tbet) promote venous thrombosis through neutrophil activation. Methods Venous thrombosis was induced by flow restriction in the inferior vena cava in IFN-gamma(-/-), Tbet(-/-) or wild-type (WT) mice. After 48 h, thrombus size was measured by the use of high-frequency ultrasound. NET formation was determined by immunofluorescence. Results and Conclusions Thrombus formation was reduced in Tbet(-/-) and IFN-gamma(-/-) mice, suggesting that Tbet/IFN-gamma-expressing cells are required for venous thrombosis. The number of NETs formed during thrombosis was significantly lower in Tbet(-/-) and IFN-gamma(-/-) mice. NET formation was also decreased in WT mice treated with an IFN-gamma-blocking antibody. Injection of recombinant IFN-gamma into IFN-gamma(-/-) mice rescued the phenotype. Natural killer (NK) cells were specifically depleted prior to venous thrombosis induction. NK cell depletion results in decreased NET formation and smaller thrombi, suggesting that NK cells are required for thrombus development. In depleted mice, adoptive transfer of WT NK cells induced a similar thrombosis burden as in WT mice. In contrast, adoptive transfer of IFN-gamma (-/-) NK cells resulted in thrombi similar in size to those in depleted mice. In vitro, we showed that WT neutrophils released fewer NETs when they were cocultured with IFN-gamma(-/-) NK cells. This study demonstrates that NK cell-dependent IFN-gamma production is crucial for thrombus development by promoting the formation of NETs by neutrophils.