GPVI signaling is compromised in newly formed platelets after acute thrombocytopenia in mice
GPVI signaling is compromised in newly formed platelets after acute thrombocytopenia in mice
复制标题
DOI：
10.1182/blood-2017-08-800136
复制
发表时间：
2018-03-08
期刊：
影响因子：
20.3
通讯作者：
Nieswandt, Bernhard
中科院分区：
文献类型：
--
作者：
Gupta, Shuchi;Cherpokova, Deya;Nieswandt, Bernhard
在血管损伤部位，暴露的内皮下胶原通过与血小板表面上的免疫受体酪氨酸活化基序（ITAM）偶联糖蛋白VI（GPVI）相互作用触发血小板活化和血栓形成。血小板来源于巨核细胞（MK）的细胞质，巨核细胞将大的前血小板延伸到骨髓（BM）窦状隙中，然后释放到血流中，在血流中发生最终的血小板大小和成熟。在富含胶原的BM环境中阻止MK活化和形成前血小板的机制在很大程度上仍然难以捉摸。在这里，我们证明，新形成的年轻血小板（NFYPs）后，抗体介导的血小板减少症小鼠显示严重的和高度选择性的信号缺陷下游的GPVI导致受损的胶原依赖性激活和血栓形成在体外和体内。NFYPs中GPVI信号的减少与关键下游信号蛋白（包括Syk、LAT和磷脂酶C γ 2）磷酸化的减少有关，而G蛋白偶联受体和C型凝集素样受体2信号通路未受影响。一旦循环中的血小板计数恢复正常，这种GPVI信号缺陷就被克服了。总体而言，这些结果表明，抗体介导的血小板减少症后NFYP中的GPVI-ITAM信号传导机制仅在血液循环中变得完全起作用。
At sites of vascular injury, exposed subendothelial collagens trigger platelet activation and thrombus formation by interacting with the immunoreceptor tyrosine-based activation motif (ITAM)-coupled glycoprotein VI (GPVI) on the platelet surface. Platelets are derived from he cytoplasm of megakaryocytes (MKs), which extend large proplatelets into bone marrow (BM) sinusoids that are then released into the bloodstream, where final platelet sizing and maturation occurs. The mechanisms that prevent activation of MKs and forming proplatelets in the collagen-rich BM environment remain largely elusive. Here, we demonstrate that newly formed young platelets (NFYPs) released after antibody-mediated thrombocytopenia in mice display a severe and highly selective signaling defect downstream of GPVI resulting in impaired collagen-dependent activation and thrombus formation in vitro and in vivo. The diminished GPVI signaling in NFYPs is linked to reduced phosphorylation of key downstream signaling proteins, including Syk, LAT, and phospholipase C gamma 2, whereas the G protein-coupled receptor and C-type lectin-like receptor 2 signaling pathways remained unaffected. This GPVI signaling defect was overcome once the platelet counts were restored to normal in the circulation. Overall, these results indicate that the GPVI-ITAM signaling machinery in NFYPs after antibody-mediated thrombocytopenia only becomes fully functional in the blood circulation.