Antiphospholipid antibody-mediated effects in an arterial model of thrombosis are dependent on Toll-like receptor 4
Antiphospholipid antibody-mediated effects in an arterial model of thrombosis are dependent on Toll-like receptor 4
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DOI：
10.1177/0961203315603146
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发表时间：
2016-02-01
期刊：
影响因子：
2.6
通讯作者：
Rauch, J.
中科院分区：
文献类型：
--
作者：
Laplante, P.;Fuentes, R.;Rauch, J.
抗磷脂综合征(APS)患者产生抗磷脂抗体(APL)，并发展成血管血栓，可能发生在动脉或静脉床上的大或小血管。另一方面，许多人会发生急性早幼粒细胞白血病，但从未发生血栓事件。在静脉和微血管血栓形成模型中，Toll样受体4(TLR4)似乎是APL介导的血栓前反应所必需的，但其在动脉血栓形成中的作用尚未被研究。在这里，我们认为APL本身不足以在动脉APS模型中引起血栓事件，并且需要伴随的先天免疫的触发(例如，TLR4激活)。我们特别证明了抗2-糖蛋白I(抗2GPI)抗体，APL的一个子集，在三氯化铁诱导的颈动脉损伤模型中，加速了C57BL/6野生型小鼠的血栓形成，而不是TLR4缺陷的小鼠。这些APL与动脉和静脉内皮细胞结合，特别是在2GPI存在的情况下，通过酶联免疫分析与人TLR4结合。与对照组相比，APL处理的小鼠的动脉内皮细胞有增强的白细胞粘附性。此外，APL对小鼠TLR4配体脂多糖(LPS)诱导的白细胞组织因子(TF)表达也有促进作用。APL还能增强脂多糖诱导的人外周血白细胞转铁蛋白的表达。我们的发现支持APL促进白细胞表达TF，以及增加白细胞与动脉内皮细胞的黏附的机制。APL阳性个体中TLR4的激活可能需要触发血栓事件。
Patients with antiphospholipid syndrome (APS) produce antiphospholipid antibodies (aPL) and develop vascular thrombosis that may occur in large or small vessels in the arterial or venous beds. On the other hand, many individuals produce aPL and yet never develop thrombotic events. Toll-like receptor 4 (TLR4) appears to be necessary for aPL-mediated prothrombotic effects in venous and microvascular models of thrombosis, but its role in arterial thrombosis has not been studied. Here, we propose that aPL alone are insufficient to cause thrombotic events in an arterial model of APS, and that a concomitant trigger of innate immunity (e.g. TLR4 activation) is required. We show specifically that anti-2-glycoprotein I (anti-2GPI) antibodies, a subset of aPL, accelerated thrombus formation in C57BL/6 wild-type, but not TLR4-deficient, mice in a ferric chloride-induced carotid artery injury model. These aPL bound to arterial and venous endothelial cells, particularly in the presence of 2GPI, and to human TLR4 by enzyme-linked immunoassay. Arterial endothelium from aPL-treated mice had enhanced leukocyte adhesion, compared to control IgG-treated mice. In addition, aPL treatment of mice enhanced expression of tissue factor (TF) in leukocytes induced by the TLR4 ligand lipopolysaccharide (LPS). aPL also enhanced LPS-induced TF expression in human leukocytes in vitro. Our findings support a mechanism in which aPL enhance TF expression by leukocytes, as well as augment adhesion of leukocytes to the arterial endothelium. The activation of TLR4 in aPL-positive individuals may be required to trigger thrombotic events.