Human Cytomegalovirus-Platelet Interaction Triggers Toll-Like Receptor 2-Dependent Proinflammatory and Proangiogenic Responses
Human Cytomegalovirus-Platelet Interaction Triggers Toll-Like Receptor 2-Dependent Proinflammatory and Proangiogenic Responses
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DOI：
10.1161/atvbaha.114.303287
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发表时间：
2014-04-01
影响因子：
8.7
通讯作者：
Soderberg-Naucler, Cecilia
中科院分区：
文献类型：
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作者：
Assinger, Alice;Kral, Julia B.;Soderberg-Naucler, Cecilia
目的人巨细胞病毒(HCMV)是一种广泛存在的病原体，与动脉粥样硬化等多种临床并发症密切相关。在初次感染和周期性病毒再激活期间，HCMV被释放到循环中，允许病毒与血小板相互作用。血小板在动脉粥样硬化的发生和发展中起重要作用，但血小板与巨细胞病毒相互作用的后果尚不清楚。方法与结果我们利用纯化的临床巨细胞病毒分离株VR1814研究了健康献血者血液中巨细胞病毒与血小板相互作用的影响。我们证明了HCMV与Toll样受体(TLR)2阳性的血小板亚群结合，导致信号转导、脱颗粒和释放促炎性CD40L、白细胞介素1和促血管生成血管内皮细胞衍生生长因子。在小鼠中，小鼠CMV激活了野生型但不是TLR2缺陷的血小板。然而，小鼠CMV刺激的野生型血小板上清液也激活了TLR2缺陷的血小板，表明激活的血小板产生了可溶性介质，触发了进一步的血小板激活，而不是TLR2的表达。使用ADP受体拮抗剂和apyrase的抑制剂研究表明，ADP的释放对于触发HCMV反应中的血小板二次激活是重要的。人巨细胞病毒激活的血小板迅速结合并激活中性粒细胞，通过内皮单分子层支持中性粒细胞的黏附和迁移。在体内模型中，小鼠巨细胞病毒可诱导小鼠全身血小板-白细胞聚集和血浆血管内皮细胞衍生生长因子表达上调，并以TLR2依赖的方式促进中性粒细胞外渗。结论巨细胞病毒是一种适应性较强的病原体，不会立即引起血栓形成。然而，HCMV与血小板的相互作用会导致促炎和促血管生成反应，从而加剧组织损伤，促进动脉粥样硬化的形成。因此，血小板可能参与了HCMV加速动脉粥样硬化的作用。
Objective Human cytomegalovirus (HCMV) is a widespread pathogen that correlates with various clinical complications, including atherosclerosis. HCMV is released into the circulation during primary infection and periodic viral reactivation, allowing virus-platelet interactions. Platelets are important in the onset and development of atherosclerosis, but the consequences of platelet-HCMV interactions are unclear.Approach and Results We studied the effects of HCMV-platelet interactions in blood from healthy donors using the purified clinical HCMV isolate VR1814. We demonstrated that HCMV bound to a Toll-like receptor (TLR) 2-positive platelet subpopulation, which resulted in signal transduction, degranulation, and release of proinflammatory CD40L and interleukin-1 and proangiogenic vascular endothelial-derived growth factor. In mice, murine CMV activated wild-type but not TLR2-deficient platelets. However, supernatant from murine CMV-stimulated wild-type platelets also activated TLR2-deficient platelets, indicating that activated platelets generated soluble mediators that triggered further platelet activation, independent of TLR2 expression. Inhibitor studies, using ADP receptor antagonists and apyrase, revealed that ADP release is important to trigger secondary platelet activation in response to HCMV. HCMV-activated platelets rapidly bound to and activated neutrophils, supporting their adhesion and transmigration through endothelial monolayers. In an in vivo model, murine CMV induced systemic upregulation of platelet-leukocyte aggregates and plasma vascular endothelial-derived growth factor in mice and showed a tendency to enhance neutrophil extravasation in a TLR2-dependent fashion.Conclusions HCMV is a well-adapted pathogen that does not induce immediate thrombotic events. However, HCMV-platelet interactions lead to proinflammatory and proangiogenic responses, which exacerbate tissue damage and contribute to atherogenesis. Therefore, platelets might contribute to the effects of HCMV in accelerating atherosclerosis.