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Macrophage heme oxygenase-1-SIRT1-p53 axis regulates sterile inflammation in liver ischemia-reperfusion injury.
Nakamura, Kojiro; Zhang, Min; Kageyama, Shoichi; Ke, Bibo; Fujii, Takehiro; Sosa, Rebecca A; Reed, Elaine F; Datta, Nakul; Zarrinpar, Ali; Busuttil, Ronald W; Araujo, Jesus A; Kupiec-Weglinski, Jerzy W.
Afiliación
  • Nakamura K; 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 M; Department of Medicine, Division of Cardiology, David Geffen School of Medicine at University of California, Los Angeles, CA 90095, USA.
  • Kageyama S; 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 B; 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 T; 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 RA; Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at University of California, Los Angeles, CA 90095, USA.
  • Reed EF; Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at University of California, Los Angeles, CA 90095, USA.
  • Datta N; 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.
  • Zarrinpar A; 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.
  • Busuttil RW; 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.
  • Araujo JA; Department of Medicine, Division of Cardiology, David Geffen School of Medicine at University of California, Los Angeles, CA 90095, USA. Electronic address: jaraujo@mednet.ucla.edu.
  • Kupiec-Weglinski JW; 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. Electronic address: jkupiec@mednet.ucla.edu.
J Hepatol ; 67(6): 1232-1242, 2017 12.
Article en En | MEDLINE | ID: mdl-28842295
ABSTRACT
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.
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Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: Daño por Reperfusión / Proteína p53 Supresora de Tumor / Hemo-Oxigenasa 1 / Sirtuina 1 / Inflamación / Hígado / Macrófagos Tipo de estudio: Prognostic_studies / Risk_factors_studies Límite: Animals / Humans Idioma: En Revista: J Hepatol Asunto de la revista: GASTROENTEROLOGIA Año: 2017 Tipo del documento: Article País de afiliación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: Daño por Reperfusión / Proteína p53 Supresora de Tumor / Hemo-Oxigenasa 1 / Sirtuina 1 / Inflamación / Hígado / Macrófagos Tipo de estudio: Prognostic_studies / Risk_factors_studies Límite: Animals / Humans Idioma: En Revista: J Hepatol Asunto de la revista: GASTROENTEROLOGIA Año: 2017 Tipo del documento: Article País de afiliación: Estados Unidos