TRAF3 negatively regulates platelet activation and thrombosis.
TRAF3 negatively regulates platelet activation and thrombosis.
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TRAF3 负向调节血小板活化和血栓形成。
DOI：
10.1038/s41598-017-17189-1
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发表时间：
2017
影响因子：
4.6
通讯作者：
Li,Zhenyu
中科院分区：
文献类型：
--
作者：
Zhang,Rui;Zhang,Guoying;Xiang,Binggang;Chen,Xiaofeng;Tang,Lijang;Shi,Shaojun;Liu,Yani;Ai,Xun;Xie,Ping;Li,Zhenyu
CD40配体(CD40L)是肿瘤坏死因子(TNF超家族)的一员，它与CD40结合，根据靶细胞类型的不同发挥多种作用。血小板表达CD40L，是可溶性CD40L的主要来源。CD40L可增强血小板活化和血栓形成，涉及CD40依赖和非依赖两种机制。一个被称为肿瘤坏死因子受体相关因子(TRAF)的蛋白质家族在介导CD40L-CD40信号转导中起关键作用。血小板表达几种TRAF。已有研究表明，TRAF2在CD40L介导的血小板活化中起作用。我们发现，血小板也表达TRAF3，TRAF3在调节血小板活化方面起着负面作用。在TRAF3基因敲除小鼠中，凝血酶或胶原诱导的血小板聚集和分泌增加。TRAF3基因缺失不影响血小板胶原受体GPVI和整合素αIIbβ3的表达水平，提示TRAF3基因敲除小鼠血小板活化增加不是由于血小板受体表达增加所致。在TRAF3基因敲除小鼠中，在FeCl3诱导的血栓形成模型中，血栓形成的时间显著缩短。然而，小鼠尾巴出血时间不受TRAF3基因缺失的影响。因此，TRAF3在体内的血小板活化和血栓形成中起着负面作用。
CD40 ligand (CD40L), a member of the tumor necrosis factor (TNF) superfamily, binds to CD40, leading to many effects depending on target cell type. Platelets express CD40L and are a major source of soluble CD40L. CD40L has been shown to potentiate platelet activation and thrombus formation, involving both CD40-dependent and -independent mechanisms. A family of proteins called TNF receptor associated factors (TRAFs) plays key roles in mediating CD40L-CD40 signaling. Platelets express several TRAFs. It has been shown that TRAF2 plays a role in CD40L-mediated platelet activation. Here we show that platelet also express TRAF3, which plays a negative role in regulating platelet activation. Thrombin- or collagen-induced platelet aggregation and secretion are increased in TRAF3 knockout mice. The expression levels of collagen receptor GPVI and integrin αIIbβ3 in platelets were not affected by deletion of TRAF3, suggesting that increased platelet activation in the TRAF3 knockout mice was not due to increased expression platelet receptors. Time to formation of thrombi in a FeCl3-induced thrombosis model was significantly shortened in the TRAF3 knockout mice. However, mouse tail-bleeding times were not affected by deletion of TRAF3. Thus, TRAF3 plays a negative role in platelet activation and in thrombus formationin vivo.