血小板 ITAM 信号对炎症中的血管完整性至关重要。,The Journal of Clinical Investigation

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血小板 ITAM 信号对炎症中的血管完整性至关重要。
The Journal of Clinical Investigation ( IF 13.3 ) Pub Date : 2013-01-25 , DOI: 10.1172/jci65154
Yacine Boulaftali ₁ , Paul R Hess , Todd M Getz , Agnieszka Cholka , Moritz Stolla , Nigel Mackman , A Phillip Owens , Jerry Ware , Mark L Kahn , Wolfgang Bergmeier

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血小板在炎症期间维持血管完整性方面起着关键作用，但对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，但不是 GPCR 信号，对于预防炎症引起的出血至关重要。为了生成在这些信号通路中具有部分或完全缺陷的小鼠，我们开发了一种将遗传和/或化学抑制的血小板过继转移到血小板减少症 (TP) 小鼠中的协议。出乎意料的是，GPCR 信号受损的血小板（血小板栓塞形成和止血的关键组成部分）在防止炎症部位出血的能力方面与 WT 血小板无法区分。相比之下，GPVI 的抑制或 Clec2 的基因缺失，小鼠血小板上唯一表达的 ITAM 受体，显着降低了血小板防止炎症引起的出血的能力。此外，将没有 ITAM 受体功能的血小板或缺乏接头蛋白 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着影响。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。将没有 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着影响。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。将没有 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着影响。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。

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Platelet ITAM signaling is critical for vascular integrity in inflammation.

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.

更新日期：2019-11-01

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