Tyro3, Axl, and Mertk receptors differentially participate in platelet activation and thrombus formation
Tyro3, Axl, and Mertk receptors differentially participate in platelet activation and thrombus formation
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Tyro3、Axl 和 Mertk 受体差异参与血小板活化和血栓形成
DOI：
10.1186/s12964-018-0308-0
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发表时间：
2018
影响因子：
8.4
通讯作者：
Wu Yi
中科院分区：
文献类型：
--
作者：
Zhou Junsong;Yang Aizhen;Wang Yucan;Chen Fengwu;Zhao Zhenzhen;Davra Viralkumar;Suzuki-Inoue Katsue;Ozaki Yukio;Birge Raymond B.;Lu Qingxian;Wu Yi
背景研究表明Tyro 3、Axl和Mertk（TAM）受体参与血小板活化和血栓形成。然而，个别受体的作用是不完全understood.MethodsUsing单受体缺陷型血小板从TAM敲除小鼠在C57 BL/6 J株，我们进行了敲除研究，使用单TAM缺陷型小鼠。我们用糖蛋白VI（GPVI）激动剂惊厥素、聚（PHG）和胶原相关三螺旋肽（CRP）以及凝血酶处理从TAM敲除小鼠中分离的血小板进行体外实验。我们使用了激光诱导的提睾肌动脉损伤模型血栓形成experimentsinvivo.ResultsDeficiency的酪氨酸激酶受体，Axl或Tyro 3，但不是Mertk，抑制聚集，扩散，JON/A结合，和P-选择素表达的血小板在体外。在体内，Axl−/−和Tyro 3 −/−小鼠的血小板血栓形成显著减少，但Mertk−/−小鼠没有。在糖蛋白VI（GPVI）激动剂刺激下，Axl−/−和Tyro 3 −/−血小板中信号分子（包括脾酪氨酸激酶（Syk）和磷脂酶C-γ2（PLCγ2））的酪氨酸磷酸化降低，但Mertk−/−血小板中没有。虽然在存在或不存在Gas 6中和抗体的情况下，由激动剂诱导的血小板聚集没有差异，但血小板聚集被抗Axl或抗Tyro 3中和抗体抗体抑制，但不被抗Mertk抗体抑制。此外，重组细胞外结构域的Axl或Tyro 3，但不是Mertk，也抑制血小板aggregation.ConclusionsThese数据表明，Axl和Tyro 3，但不是Mertk，有一个重要的作用，在血小板活化和血栓形成，和机械可能这样做的一个途径，调节内到外的信号和异型相互作用，通过细胞外结构域的TAM。
BackgroundPreviously, several studies have shown that Tyro3, Axl, and Mertk (TAM) receptors participate in platelet activation and thrombosis. However, the role of individual receptors is not fully understood.MethodsUsing single receptor-deficient platelets from TAM knockout mice in the C57BL/6 J strain, we performed a knockout study using single TAM-deficient mice. We treated platelets isolated from TAM knockout mice with the Glycoprotein VI (GPVI) agonists convulxin, poly(PHG), and collagen-related triple-helical peptide (CRP), as well as thrombin for in-vitro experiments. We used a laser-induced cremaster arterial injury model for thrombosis experiments in vivo.ResultsDeficiency of the tyrosine kinase receptors, Axl or Tyro3, but not Mertk, inhibited aggregation, spreading, JON/A binding, and P-selectin expression of platelets in vitro. In vivo, platelet thrombus formation was significantly decreased in Axl−/−and Tyro3−/−mice, but not in Mertk−/−mice. Upon stimulation with glycoprotein VI (GPVI) agonists, tyrosine phosphorylation of signaling molecules, including spleen tyrosine kinase (Syk) and phospholipase C-γ2 (PLCγ2), was decreased in Axl−/−and Tyro3−/−platelets, but not in Mertk−/−platelets. While platelet aggregation induced by agonists did not differ in the presence or absence of the Gas6 neutralizing antibody, the platelet aggregation was inhibited by anti-Axl or anti-Tyro3 neutralizing antibodies antibody, but not the anti-Mertk antibody. Additionally, the recombinant extracellular domain of Axl or Tyro3, but not that of Mertk, also inhibited platelet aggregation.ConclusionsThese data suggest that Axl and Tyro3, but not Mertk, have an important role in platelet activation and thrombus formation, and mechanistically may do so by a pathway that regulates inside to outside signaling and heterotypic interactions via the extracellular domains of TAMs.