Cooperative PSGL-1 and CXCR2 signaling in neutrophils promotes deep vein thrombosis in mice
Cooperative PSGL-1 and CXCR2 signaling in neutrophils promotes deep vein thrombosis in mice
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DOI：
10.1182/blood-2018-05-850859
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发表时间：
2018-09-27
期刊：
影响因子：
20.3
通讯作者：
McEver, Rodger P.
中科院分区：
文献类型：
--
作者：
Yago, Tadayuki;Liu, Zhenghui;McEver, Rodger P.
炎症是深静脉血栓形成的主要原因。小鼠下腔静脉（IVC）限流诱导深静脉血栓形成，与人类相似。在该模型中，中性粒细胞和单核细胞的p选择不依赖粘附导致中性粒细胞胞外陷阱（NETs）的释放和组织因子的表达。然而，目前尚不清楚是什么信号导致骨髓细胞产生这些促凝效应物。通过对基因工程小鼠进行超声检查和旋转盘活体显微镜观察，我们发现p选择素糖蛋白配体-1 （PSGL-1）和趋化因子受体CXCR2参与滚动中性粒细胞传播信号，这些信号共同诱导血流受限的IVCs中β 2整合素依赖性停搏。与之前的报道不同，中性粒细胞中的PSGL-1信号不需要l -选择素，它在含有76 kDa的适配器Src同源结构域的白细胞磷酸化蛋白上使用酪氨酸145而不是酪氨酸112和128。PSGL-1和CXCR2信号共同增加血栓发生的频率和大小，部分原因是通过刺激NETs的释放。与中性粒细胞不同，阻断单核细胞中的PSGL-1或CXCR2信号传导并不影响它们向血栓募集或组织因子的表达。我们的研究结果表明，中性粒细胞通过PSGL-1和CXCR2协同信号促进DVT。
Inflammation is a major contributor to deep vein thrombosis (DVT). Flow restriction of the inferior vena cava (IVC) in mice induces DVT like that in humans. In this model, P-selectindependent adhesion of neutrophils and monocytes leads to release of neutrophil extracellular traps (NETs) and expression of tissue factor. However, it is not known what signals cause myeloid cells to generate these procoagulant effectors. Using ultrasonography and spinningdisk intravital microscopy in genetically engineered mice, we found that engagement of P-selectin glycoprotein ligand-1 (PSGL-1) and the chemokine receptor CXCR2 on rolling neutrophils propagated signals that cooperated to induce beta 2 integrin-dependent arrest in flow-restricted IVCs. Unlike previous reports, PSGL-1 signaling in neutrophils did not require L-selectin, and it used tyrosine 145 rather than tyrosines 112 and 128 on the adaptor Src homology domain-containing leukocyte phosphoprotein of 76 kDa. PSGL-1 and CXCR2 signaling cooperated to increase the frequency and size of thrombi, in part by stimulating release of NETs. Unlike in neutrophils, blocking PSGL-1 or CXCR2 signaling in monocytes did not affect their recruitment into thrombi or their expression of tissue factor. Our results demonstrate that neutrophils cooperatively signal through PSGL-1 and CXCR2 to promote DVT.