Deletion of CD39 on natural killer cells attenuates hepatic ischemia/reperfusion injury in mice

Authors

  • Guido Beldi,

    1. Liver Center and Transplantation Institute, Department of Medicine and Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA
    2. Department of Visceral and Transplant Surgery, Inselspital, University Hospital, Bern, Switzerland
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  • Yara Banz,

    1. Liver Center and Transplantation Institute, Department of Medicine and Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA
    2. Institute of Pathology, University of Bern, Switzerland
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  • Alexander Kroemer,

    1. Liver Center and Transplantation Institute, Department of Medicine and Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA
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  • Xiaofeng Sun,

    1. Liver Center and Transplantation Institute, Department of Medicine and Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA
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  • Yan Wu,

    1. Liver Center and Transplantation Institute, Department of Medicine and Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA
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  • Nadine Graubardt,

    1. Department of Visceral and Transplant Surgery, Inselspital, University Hospital, Bern, Switzerland
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  • Alyssa Rellstab,

    1. Department of Visceral and Transplant Surgery, Inselspital, University Hospital, Bern, Switzerland
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  • Martina Nowak,

    1. Liver Center and Transplantation Institute, Department of Medicine and Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA
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  • Keiichi Enjyoji,

    1. Liver Center and Transplantation Institute, Department of Medicine and Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA
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  • Xian Li,

    1. Liver Center and Transplantation Institute, Department of Medicine and Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA
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  • Wolfgang G. Junger,

    1. Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA
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  • Daniel Candinas,

    1. Department of Visceral and Transplant Surgery, Inselspital, University Hospital, Bern, Switzerland
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  • Simon C. Robson

    Corresponding author
    1. Liver Center and Transplantation Institute, Department of Medicine and Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA
    • Transplant Center, Hepatology, 330 Brookline Avenue, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston MA 02215
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    • fax: 617-735-2930.


  • Potential conflict of interest: Nothing to report.

Abstract

Natural killer (NK) cells play crucial roles in innate immunity and express CD39 (Ecto-nucleoside triphosphate diphosphohydrolase 1 [E-NTPD1]), a rate-limiting ectonucleotidase in the phosphohydrolysis of extracellular nucleotides to adenosine. We have studied the effects of CD39 gene deletion on NK cells in dictating outcomes after partial hepatic ischemia/reperfusion injury (IRI). We show in mice that gene deletion of CD39 is associated with marked decreases in phosphohydrolysis of adenosine triphosphate (ATP) and adenosine diphosphate to adenosine monophosphate on NK cells, thereby modulating the type-2 purinergic (P2) receptors demonstrated on these cells. We note that CD39-null mice are protected from acute vascular injury after single-lobe warm IRI, and, relative to control wild-type mice, display significantly less elevation of aminotransferases with less pronounced histopathological changes associated with IRI. Selective adoptive transfers of immune cells into Rag2/common gamma null mice (deficient in T cells, B cells, and NK/NKT cells) suggest that it is CD39 deletion on NK cells that provides end-organ protection, which is comparable to that seen in the absence of interferon gamma. Indeed, NK effector mechanisms such as interferon gamma secretion are inhibited by P2 receptor activation in vitro. Specifically, ATPγS (a nonhydrolyzable ATP analog) inhibits secretion of interferon gamma by NK cells in response to interleukin-12 and interleukin-18, providing a mechanistic link between CD39 deletion and altered cytokine secretion. Conclusion: We propose that CD39 deficiency and changes in P2 receptor activation abrogate secretion of interferon gamma by NK cells in response to inflammatory mediators, thereby limiting tissue damage mediated by these innate immune cells during IRI. (HEPATOLOGY 2010.)

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