A critical role of the Gas6-Mer axis in endothelial dysfunction contributing to TA-TMA associated with GVHD
A critical role of the Gas6-Mer axis in endothelial dysfunction contributing to TA-TMA associated with GVHD
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DOI：
10.1182/bloodadvances.2019000222
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发表时间：
2019-07-23
期刊：
影响因子：
7.5
通讯作者：
Ikezoe, Takayuki
中科院分区：
文献类型：
--
作者：
Furukawa, Miki;Wang, Xintao;Ikezoe, Takayuki
造血干细胞移植（HSCT）早期的内皮功能障碍导致移植相关血栓性微血管病（TA-TMA）和移植物抗宿主病（GVHD）之间的共同病理，这是HSCT的严重并发症。生长停滞特异性（Gas）6在结构上属于血浆维生素K依赖性蛋白家族，作为活化蛋白C的辅因子，并通过与TAM家族的受体酪氨酸激酶Tyro 3、Axl和Mer相互作用而具有生长因子样特性。血清Gas 6水平在患有II至IV级急性GVHD（aGVHD）的HSCT患者中显著升高，并且Gas 6和Mer表达水平在大肠和皮肤的aGVHD病变中上调。血清Gas 6水平升高也与aGVHD HSCT患者中乳酸脱氢酶、D-二聚体和纤溶酶抑制剂复合物值升高相关。在人脐静脉内皮细胞（ECs）中，外源性Gas 6或Ⅲ度aGVHD患者血清暴露于ECs可诱导血栓调节蛋白（thrombomodulin）下调和派-1上调，以及细胞间粘附分子（ICAM-1）和血管细胞粘附分子（vascular cell adhesion molecule-1）上调，而选择性Mer酪氨酸激酶抑制剂UNC 2250可抑制这些上调。在小鼠HSCT模型中，我们观察到肝GVHD伴肝细胞凋亡、坏死和纤维化，以及TA-TMA，其病理特征为肝和肾的微血管中血栓形成。值得注意的是，静脉给予UNC 2250显著抑制了这些小鼠HSCT模型中的GVHD和TA-TMA。我们的研究结果表明Gas 6-Mer轴是GVHD后TA-TMA的一个有希望的靶点。
Endothelial dysfunction in the early phases of hematopoietic stem cell transplantation (HSCT) contributes to a common pathology between transplant-associated thrombotic microangiopathy (TA-TMA) and graft-versus-host disease (GVHD), which are serious complications of HSCT. Growth arrest-specific (Gas) 6 structurally belongs to the family of plasma vitamin K-dependent proteins working as a cofactor for activated protein C, and has growth factor-like properties through its interaction with receptor tyrosine kinases of the TAM family: Tyro3, Axl, and Mer. Serum Gas6 levels were significantly increased in HSCT patients with grade II to IV acute GVHD (aGVHD), and Gas6 and Mer expression levels were upregulated in aGVHD lesions of the large intestine and skin. The increased serum Gas6 levels were also correlated with elevated lactate dehydrogenase, D-dimer, and plasmin inhibitor complex values in HSCT patients with aGVHD. In human umbilical vein endothelial cells (ECs), exogenous Gas6 or the exposure of sera isolated from patients with grade III aGVHD to ECs induced the downregulation of thrombomodulin and the upregulation of PAI-1, as well as the upregulation of intercellular adhesion molecule-1 and vascular cell adhesion molecule-1, which were inhibited by UNC2250, a selective Mer tyrosine kinase inhibitor. In mouse HSCT models, we observed hepatic GVHD with hepatocellular apoptosis, necrosis, and fibrosis, as well as TA-TMA, which is characterized pathologically by thrombosis formation in the microvasculature of the liver and kidney. Of note, intravenous administration of UNC2250 markedly suppressed GVHD and TA-TMA in these mouse HSCT models. Our findings suggest that the Gas6-Mer axis is a promising target for TA-TMA after GVHD.