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Macrophage heme oxygenase-1-SIRT1-p53 Axis Regulates Sterile Inflammation in Liver Ischemia-Reperfusion Injury
Journal of Hepatology ( IF 25.7 ) Pub Date : 2017-12-01 , DOI: 10.1016/j.jhep.2017.08.010
Kojiro Nakamura , Min Zhang , Shoichi Kageyama , Bibo Ke , Takehiro Fujii , Rebecca A. Sosa , Elaine F. Reed , Nakul Datta , Ali Zarrinpar , Ronald W. Busuttil , Jesus A. Araujo , Jerzy W. Kupiec-Weglinski

BACKGROUND & AIMS 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. METHODS 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. RESULTS 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. CONCLUSION 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. LAY SUMMARY 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.

中文翻译:

巨噬细胞血红素加氧酶-1-SIRT1-p53 轴调节肝脏缺血再灌注损伤中的无菌炎症

背景与目的 肝缺血再灌注损伤 (IRI) 的特点是外源性抗原非依赖性局部炎症和肝细胞死亡,是肝移植急性和慢性排斥反应的危险因素。我们旨在研究参与肝脏 IRI 机制的分子通讯。方法 我们分析了骨髓特异性血红素加氧酶-1 (HO-1) 基因突变小鼠的人肝移植、原代小鼠巨噬细胞培养物和 IR 应激肝脏,以了解巨噬细胞特异性 HO-1/SIRT1 的抗炎和细胞保护功能(sirtuin 1)/p53(肿瘤抑制蛋白)信号。结果 人再灌注后肝移植活检组织中 HO-1 表达的降低与肝细胞功能的恶化(血清 ALT;p<0.05)和患者存活率下降(p<0.05)相关。在低 HO-1 肝移植活检组中,SIRT1/Arf(替代阅读框)/p53/MDM2(鼠双分钟 2)表达水平降低(p<0.05),同时裂解的 caspase 3 和 TUNEL+细胞频率增加( p<0.05)。免疫荧光显示巨噬细胞是人和小鼠 IR 应激肝脏中 HO-1 的主要来源。体外巨噬细胞培养显示 HO-1 诱导正调节 SIRT1 信号传导,而 SIRT1 诱导的 Arf 抑制 MDM2 对 p53 的泛素化活性,从而减弱巨噬细胞活化。在肝脏温暖 IRI 的小鼠模型中,骨髓特异性 HO-1 缺失缺乏 SIRT1/p53,加剧了肝脏炎症和 IR 肝细胞死亡,而辅助 SIRT1 激活恢复了 p53 信号传导并使肝脏免于 IR 损伤。结论这项从工作台到床边的研究在肝脏无菌性炎症的机制中确定了一类通过 HO-1-SIRT1-p53 信号轴激活的新巨噬细胞。这种机制可能是肝移植受者新治疗策略的目标。概述 移植后人肝移植中巨噬细胞 HO-1 的低表达与肝细胞功能和存活率降低相关。HO-1 通过 SIRT1-p53 信号网络调节巨噬细胞活化并调节肝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。这种机制可能是肝移植受者新治疗策略的目标。概述 移植后人肝移植中巨噬细胞 HO-1 的低表达与肝细胞功能和存活率降低相关。HO-1 通过 SIRT1-p53 信号网络调节巨噬细胞活化并调节肝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。这种机制可能是肝移植受者新治疗策略的目标。概述 移植后人肝移植中巨噬细胞 HO-1 的低表达与肝细胞功能和存活率降低相关。HO-1 通过 SIRT1-p53 信号网络调节巨噬细胞活化并调节肝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。
更新日期:2017-12-01
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