Activated AXL Protects Against Hepatic Ischemia-reperfusion Injury by Upregulating SOCS-1 Expression.
Activated AXL Protects Against Hepatic Ischemia-reperfusion Injury by Upregulating SOCS-1 Expression.
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激活的 AXL 通过上调 SOCS-1 表达来预防肝缺血再灌注损伤
DOI：
10.1097/tp.0000000000004156
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发表时间：
2022-07-01
期刊：
影响因子：
6.2
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中科院分区：
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肝缺血再灌注(I/R)损伤是影响肝移植和肝大部切除术围手术期并发症发生率和死亡率的主要因素。AXL是Tyro3、AXL、MERTK家族的成员，参与多个器官的免疫和细胞凋亡过程。然而，Axl在肝脏I/R损伤中的作用尚不清楚。用rmGas6或R428处理的小鼠和尾静脉注射细胞因子信号蛋白1的腺相关病毒抑制物(SoCS-1)的小鼠在肝脏I/R手术中检测激活的Ax1的功能。原代肝细胞在体外经历低氧复氧损伤。在肝移植患者和肝I/R手术小鼠中，AXL的表达显著上调，而磷酸化的AXL显著下调。小鼠肝脏I/R损伤模型显示Axl激活可减少肝脏炎症和肝细胞凋亡。抑制Axl激活(Axl特异性抑制剂R428)加重了肝脏I/R损伤，导致肝脏损伤面积扩大，炎症反应加重，肝细胞凋亡增加。此外，激活的Axl可促进SOCS-1的表达，抑制Toll样受体4及其下游信号通路。最后，SOCS-1被腺相关病毒击倒，激活的Axl未能保护肝脏I/R损伤。AXL的激活通过上调SOCS-1和抑制Toll样受体4/髓系分化因子-88/核因子-kappa-B信号轴来保护肝脏免受I/R损伤。靶向Axl可能是改善肝脏I/R损伤的一种新的治疗选择。
Hepatic ischemia-reperfusion (I/R) injury is the main factor affecting the morbidity and mortality associated with perioperative complications of liver transplantation and major hepatectomy. AXL is a member of the TYRO3, AXL, MERTK family and is involved in immune and apoptosis processes in multiple organs. However, the role of AXL in hepatic I/R injury remains to be elucidated. Mice pretreated with rmGas6 or R428 and mice tail vein injected with adeno-associated virus knockdown suppressor of cytokine signaling protein-1 (SOCS-1) underwent liver I/R surgery to detect the function of activated AXL in vivo. Primary hepatocytes undergo hypoxic reoxygenation injury in vitro. AXL expression was significantly upregulated, and phosphorylated-AXL was substantially downregulated in liver transplantation patients and hepatic I/R surgery mice. A mouse model of hepatic I/R injury showed that AXL activation reduced liver inflammation and liver cells apoptosis. The inhibition of AXL activation (AXL-specific inhibitor R428) aggravated hepatic I/R injury, resulted in larger areas of liver injury, aggravated inflammatory response, and increased apoptosis of liver cells. In addition, activated AXL promotes the expression level of SOCS-1 and inhibits toll-like receptor 4 and its downstream signaling pathways. Finally, SOCS-1 was knocked down with an adeno-associated virus, and activated AXL failed to protect against hepatic I/R injury. AXL activation protects the liver from I/R injury by upregulating SOCS-1 and inhibiting the toll-like receptor 4/myeloid differentiation factor-88/nuclear factor kappa-B signaling axis. Targeting AXL may be a new therapeutic option for ameliorating hepatic I/R injury.