Macrophage heme oxygenase-1-SIRT1-p53 axis regulates sterile inflammation in liver ischemia-reperfusion injury.
Macrophage heme oxygenase-1-SIRT1-p53 axis regulates sterile inflammation in liver ischemia-reperfusion injury.
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DOI：
10.1016/j.jhep.2017.08.010
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发表时间：
2017-12
影响因子：
25.7
通讯作者：
Kupiec-Weglinski JW
中科院分区：
文献类型：
--
作者：
Nakamura K;Zhang M;Kageyama S;Ke B;Fujii T;Sosa RA;Reed EF;Datta N;Zarrinpar A;Busuttil RW;Araujo JA;Kupiec-Weglinski JW
肝缺血再灌注损伤（IRI）是肝移植术后发生急性和慢性排斥反应的危险因素，其特征为外源性抗原非依赖性局部炎症反应和肝细胞死亡。我们的目的是研究肝脏IRI机制中的分子通讯。我们分析了人肝移植，原代小鼠巨噬细胞培养物和骨髓特异性血红素加氧酶-1（HO-1）基因突变小鼠的IR应激肝脏，巨噬细胞特异性HO-1/SIRT 1（沉默调节蛋白1）/p53（肿瘤抑制蛋白）信号传导的抗炎和细胞保护功能。人肝移植再灌注后活组织切片中HO-1表达的降低与肝细胞功能恶化（血清ALT; p <0.05）和患者生存率降低（p <0.05）相关。在低HO-1肝移植活检组中，SIRT 1/Arf（交替阅读框架）/p53/MDM 2（小鼠双微体2）表达水平降低（p <0.05），而切割的caspase 3和TUNEL +细胞频率同时增加（p <0.05）。免疫荧光显示巨噬细胞是人和小鼠IR应激肝脏HO-1的主要来源。体外巨噬细胞培养显示，HO-1诱导正调控SIRT 1信号，而SIRT 1诱导的Arf抑制MDM 2对p53的泛素化活性，这反过来又减弱了巨噬细胞活化。在小鼠肝脏温热IRI模型中，骨髓特异性HO-1缺失缺乏SIRT 1/p53，加重肝脏炎症和IR-肝细胞死亡，而连续性SIRT 1激活恢复p53信号传导并拯救肝脏免受IR-损伤。这项实验室到床边的研究确定了一类新的巨噬细胞通过HO-1-SIRT 1-p53信号轴在肝脏无菌性炎症机制中活化。这一机制可能成为肝移植受者新的治疗策略的靶点。人肝移植后低巨噬细胞HO-1表达与肝细胞功能和存活率降低相关。HO-1通过SIRT 1-p53信号网络调节巨噬细胞活化并调节肝脏缺血再灌注损伤中的肝细胞死亡。因此，在肝移植受者中靶向该途径可能具有治疗益处。
Hepatic ischemia-reperfusion injury (IRI), characterized by exogenous antigen-independent local inflammation and hepatocellular death, represents a risk factor for acute and chronic rejection in liver transplantation. We aimed to investigate the molecular communication involved in the mechanism of liver IRI. We analyzed human liver transplants, primary murine macrophage cell cultures and IR-stressed livers in myeloid-specific heme oxygenase-1 (HO-1) gene mutant mice, for anti-inflammatory and cytoprotective functions of macrophage-specific HO-1/SIRT1 (sirtuin 1)/p53 (tumor suppressor protein) signaling. Decreased HO-1 expression in human post-reperfusion liver transplant biopsies correlated with a deterioration in hepatocellular function (serum ALT; p <0.05) and inferior patient survival (p <0.05). In the low HO-1 liver transplant biopsy group, SIRT1/Arf (alternative reading frame)/p53/MDM2 (murine double minute 2) expression levels decreased (p <0.05) while cleaved caspase 3 and frequency of TUNEL + cells simultaneously increased (p <0.05). Immunofluorescence showed macrophages were the principal source of HO-1 in human and mouse IR-stressed livers. In vitro macrophage cultures revealed that HO-1 induction positively regulated SIRT1 signaling, whereas SIRT1-induced Arf inhibited ubiquitinating activity of MDM2 against p53, which in turn attenuated macrophage activation. In a murine model of hepatic warm IRI, myeloid-specific HO-1 deletion lacked SIRT1/p53, exacerbated liver inflammation and IR-hepatocellular death, whereas adjunctive SIRT1 activation restored p53 signaling and rescued livers from IR-damage. This bench-to-bedside study identifies a new class of macrophages activated via the HO-1–SIRT1–p53 signaling axis in the mechanism of hepatic sterile inflammation. This mechanism could be a target for novel therapeutic strategies in liver transplant recipients. Post-transplant low macrophage HO-1 expression in human liver transplants correlates with reduced hepatocellular function and survival. HO-1 regulates macrophage activation via the SIRT1–p53 signaling network and regulates hepatocellular death in liver ischemia-reperfusion injury. Thus targeting this pathway in liver transplant recipients could be of therapeutic benefit.
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小鼠肝脏中 Sirt1 的失活可通过乙酰化和激活 NF-kappaB 来防止内毒素血症性肝损伤。
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作者：
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通讯作者：
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