Cellular fibronectin containing extra domain A promotes arterial thrombosis in mice through platelet Toll-like receptor 4
Cellular fibronectin containing extra domain A promotes arterial thrombosis in mice through platelet Toll-like receptor 4
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DOI：
10.1182/blood-2014-10-608653
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发表时间：
2015-05-14
期刊：
影响因子：
20.3
通讯作者：
Chauhan, Anil K.
中科院分区：
文献类型：
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作者：
Prakash, Prem;Kulkarni, Paresh P.;Chauhan, Anil K.
含有额外结构域的细胞纤维连接蛋白(FN-EDA+)是在多种疾病状态下对组织损伤作出反应时产生的，具有促血栓形成活性，并已知与Toll样受体4(TLR4)相互作用。FN-EDA+参与介导血栓前反应的机制和细胞类型尚不清楚。利用活体显微镜，我们评估了表达FN缺乏EDA的小鼠(FN-EDA(-/-)小鼠)或表达FN的EDA(+/+)小鼠(FN-EDA(+/+)小鼠)在FeCl3诱导的损伤后颈动脉血栓形成的敏感性。FN-EDA(-/-)小鼠首次血栓形成和完全闭塞的时间延长，血栓生长速度显著降低(P<；0.05与FN-EDA(+/+)小鼠相比)。TLR4基因缺失可逆转FN-EDA(+/+)小鼠加速的血栓形成(P<；0.05)，但对FN-EDA(-/-)小鼠无影响。骨髓移植实验表明，表达于造血细胞上的TLR4可加速FN-EDA(+/+)小鼠的血栓形成。体外研究表明，细胞内FN-EDA+与血小板TLR4相互作用，促进激动剂诱导的血小板聚集。最后，缺乏血小板TLR4的FN-EDA(+/+)小鼠首次血栓形成和完全闭塞的时间延长(P<；0.05与含有血小板TLR4的FN-EDA(+/+)小鼠相比)。我们的结论是，血小板TLR4参与了细胞FN-EDA+的血栓前效应，提示血栓形成与天然免疫之间存在另一种联系。
Cellular fibronectin containing extra domain A(Fn-EDA+), which is produced in response to tissue injury in several disease states, has prothrombotic activity and is known to interact with Toll-like-receptor 4 (TLR4). The underlying mechanism and cell types involved in mediating the prothrombotic effect of Fn-EDA+ still remain unknown. Using intravital microscopy, we evaluated susceptibility to carotid artery thrombosis after FeCl3-induced injury in mice expressing Fn lacking EDA (Fn-EDA(-/-) mice) or Fn containing EDA (Fn-EDA(+/+) mice). Fn-EDA(-/-) mice exhibited prolonged times to first thrombus formation and complete occlusion and a significant decrease in the rate of thrombus growth (P < .05 vs Fn-EDA(+/+) mice). Genetic deletion of TLR4 reversed the accelerated thrombosis in Fn-EDA(+/+) mice (P < .05) but had no effect in Fn-EDA(-/-) mice. Bone marrow transplantation experiments revealed that TLR4 expressed on hematopoietic cells contributes to accelerated thrombosis in Fn-EDA(+/+) mice. In vitro studies showed that cellular Fn-EDA+ interacts with platelet TLR4 and promotes agonist-induced platelet aggregation. Finally, Fn-EDA(+/+) mice specifically lacking platelet TLR4 exhibited prolonged times to first thrombus formation and complete occlusion (P < .05 vs Fn-EDA(+/+) mice containing platelet TLR4). We conclude that platelet TLR4 contributes to the prothrombotic effect of cellular Fn-EDA+, suggesting another link between thrombosis and innate immunity.