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Molecular Medicine

, Volume 20, Issue 1, pp 448–455 | Cite as

Adoptive Transfer of Heme Oxygenase-1 (HO-1)-Modified Macrophages Rescues the Nuclear Factor Erythroid 2-Related Factor (Nrf2) Antiinflammatory Phenotype in Liver Ischemia/Reperfusion Injury

  • Jing Huang
  • Xiu-Da Shen
  • Shi Yue
  • Jianjun Zhu
  • Feng Gao
  • Yuan Zhai
  • Ronald W. Busuttil
  • Bibo Ke
  • Jerzy W. Kupiec-Weglinski
Research Article

Abstract

Macrophages are instrumental in the pathophysiology of liver ischemia/reperfusion injury (IRI). Although Nrf2 regulates macrophage-specific heme oxygenase-1 (HO-1) antioxidant defense, it remains unknown whether HO-1 induction might rescue macrophage Nrf2-dependent antiinflammatory functions. This study explores the mechanisms by which the Nrf2-HO-1 axis regulates sterile hepatic inflammation responses after adoptive transfer of ex vivo modified HO-1 overexpressing bone marrow-derived macrophages (BMMs). Livers in Nrf2-deficient mice preconditioned with Ad-HO-1 BMMs, but not Ad-β-Gal-BMMs, ameliorated liver IRI (at 6 h of reperfusion after 90 min of warm ischemia), evidenced by improved hepatocellular function (serum alanine aminotransferase (sALT) levels) and preserved hepatic architecture (Suzuki histological score). Treatment with Ad-HO-1 BMMs decreased neutrophil accumulation, proinflammatory mediators and hepatocellular necrosis/apoptosis in ischemic livers. Moreover, Ad-HO-1 transfection of Nrf2-deficient BMMs suppressed M1 (Nos2+) while promoting the M2 (Mrc-1/Arg-1+) phenotype. Unlike in controls, Ad-HO-1 BMMs increased the expression of Notch1, Hes1, phosphorylation of Stat3 and Akt in IR-stressed Nrf2-deficient livers as well as in lipopolysaccharide (LPS)-stimulated BMMs. Thus, adoptive transfer of ex vivo generated Ad-HO-1 BMMs rescued Nrf2-dependent antiinflammatory phenotype by promoting Notch1/Hes1/Stat3 signaling and reprogramming macrophages toward the M2 phenotype. These findings provide the rationale for a novel clinically attractive strategy to manage IR liver inflammation/damage.

Notes

Acknowledgments

This work was supported by National Institutes of Health Grant DK 062357 and the W.M. Keck, Diann Kim and Dumont Research Foundations.

Supplementary material

10020_2014_2001448_MOESM1_ESM.pdf (1.6 mb)
Supplementary material, approximately 1679 KB.

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Authors and Affiliations

  • Jing Huang
    • 1
  • Xiu-Da Shen
    • 1
  • Shi Yue
    • 1
  • Jianjun Zhu
    • 1
  • Feng Gao
    • 1
  • Yuan Zhai
    • 1
  • Ronald W. Busuttil
    • 1
  • Bibo Ke
    • 1
  • Jerzy W. Kupiec-Weglinski
    • 1
  1. 1.Department of Surgery, David Geffen School of Medicine at UCLADumont-UCLA Transplant CenterLos AngelesUSA

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