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Journal of hepatology : the journal of the European Association for the Study of the Liver v.67 no.6, 2017년, pp.1232 - 1242   SCI SCIE
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Macrophage heme oxygenase-1-SIRT1-p53 axis regulates sterile inflammation in liver ischemia-reperfusion injury

Nakamura, Kojiro (The Dumont-UCLA Transplantation Center, Department of Surgery, Division of Liver and Pancreas Transplantation, David Geffen School of Medicine at University of California, Los Angeles, CA 90095, USA ) ; Zhang, Min (Department of Medicine, Division of Cardiology, David Geffen School of Medicine at University of California, Los Angeles, CA 90095, USA ) ; Kageyama, Shoichi (The Dumont-UCLA Transplantation Center, Department of Surgery, Division of Liver and Pancreas Transplantation, David Geffen School of Medicine at University of California, Los Angeles, CA 90095, USA ) ; Ke, Bibo (The Dumont-UCLA Transplantation Center, Department of Surgery, Division of Liver and Pancreas Transplantation, David Geffen School of Medicine at University of California, Los Angeles, CA 90095, USA ) ; Fujii, Takehiro (The Dumont-UCLA Transplantation Center, Department of Surgery, Division of Liver and Pancreas Transplantation, David Geffen School of Medicine at University of California, Los Angeles, CA 90095, USA ) ; Sosa, Rebecca A. (Department of Pathology and Laboratory Medicine, David Gef ) ; Reed, Elaine F. ; Datta, Nakul ; Zarrinpar, Ali ; Busuttil, Ronald W. ; Araujo, Jesus A. ; Kupiec-Weglinski, Jerzy W. ;
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    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 p p p 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. Highlights HO-1 is expressed primarily by ischemia-stressed liver macrophages. HO-1 regulates macrophage activation via SIRT1–p53 signaling. HO-1 regulates hepatocellular death in liver ischemia-reperfusion injury. Low macrophage HO-1 levels correlate with reduced human liver transplant function. Graphical abstract [DISPLAY OMISSION]


  • 주제어

    Heme oxygenase-1 .   Sirtuin 1 .   P53 .   Ischemia-reperfusion injury .   Liver transplantation .   Innate immunity .   Myeloid-specific mutant mice.  

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