Platelet ITAM signaling is critical for vascular integrity in inflammation
Platelet ITAM signaling is critical for vascular integrity in inflammation
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DOI：
10.1172/jci65154
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发表时间：
2013-02-01
影响因子：
15.9
通讯作者：
Bergmeier, Wolfgang
中科院分区：
文献类型：
--
作者：
Boulaftali, Yacine;Hess, Paul R.;Bergmeier, Wolfgang
血小板在炎症过程中维持血管完整性中起着关键作用，但对其潜在的分子机制知之甚少。在这里，我们报告，血小板免疫受体酪氨酸激活基序（ITAM）信号，而不是GPCR信号，是至关重要的预防炎症引起的出血。为了产生在这些信号通路中具有部分或完全缺陷的小鼠，我们开发了用于将遗传和/或化学抑制的血小板过继转移到血小板减少（TP）小鼠中的方案。出乎意料的是，GPCR信号传导受损的血小板（血小板栓形成和止血的关键组分）在预防炎症部位出血的能力方面与WT血小板无法区分。相反，抑制GPVI或基因缺失Clec 2（小鼠血小板上表达的唯一ITAM受体）显著降低了血小板预防炎症诱导出血的能力。此外，没有ITAM受体功能的血小板或缺乏衔接蛋白SLP-76的血小板输注到TP小鼠中对炎症期间的血管完整性没有显著影响。这些结果表明，血管完整性的控制是血小板中免疫型受体的主要功能，突出了针对ITAM信号通路的新型抗血栓药物的潜在临床并发症。
Platelets play a critical role in maintaining vascular integrity during inflammation, but little is known about the underlying molecular mechanisms. Here we report that platelet immunoreceptor tyrosine activation motif (ITAM) signaling, but not GPCR signaling, is critical for the prevention of inflammation-induced hemorrhage. To generate mice with partial or complete defects in these signaling pathways, we developed a protocol for adoptive transfer of genetically and/or chemically inhibited platelets into thrombocytopenic (TP) mice. Unexpectedly, platelets with impaired GPCR signaling, a crucial component of platelet plug formation and hemostasis, were indistinguishable from WT platelets in their ability to prevent hemorrhage at sites of inflammation. In contrast, inhibition of GPVI or genetic deletion of Clec2, the only ITAM receptors expressed on mouse platelets, significantly reduced the ability of platelets to prevent inflammation-induced hemorrhage. Moreover, transfusion of platelets without ITAM receptor function or platelets lacking the adapter protein SLP-76 into TP mice had no significant effect on vascular integrity during inflammation. These results indicate that the control of vascular integrity is a major function of immune-type receptors in platelets, highlighting a potential clinical complication of novel antithrombotic agents directed toward the ITAM signaling pathway.