Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand on NK Cells Protects From Hepatic Ischemia-Reperfusion Injury

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2014
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Fahrner, René
Trochsler, Markus
Corazza, Nadia
Graubardt, Nadine
Keogh, Adrian
Candinas, Daniel
Stroka, Deborah
Beldi, Guido
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Transplantation. 2014, 97(11), pp. 1102-1109. ISSN 0041-1337. eISSN 1534-6080. Available under: doi: 10.1097/TP.0000000000000101
Zusammenfassung

Background
Ischemia-reperfusion injury (IRI) significantly contributes to graft dysfunction after liver transplantation. Natural killer (NK) cells are crucial innate effector cells in the liver and express tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), a potent inducer of hepatocyte cell death. Here, we investigated if TRAIL expression on NK cells contributes to hepatic IRI.

Methods
The outcome after partial hepatic IRI was assessed in TRAIL-null mice and contrasted to C57BL/6J wild-type mice and after NK cell adoptive transfer in RAG2/common gamma-null mice that lack T, B, and NK cells. Liver IRI was assessed by histological analysis, alanine aminotransferase, hepatic neutrophil activation by myeloperoxidase activity, and cytokine secretion at specific time points. NK cell cytotoxicity and differentiation were assessed in vivo and in vitro.

Results
Twenty-four hours after reperfusion, TRAIL-null mice exhibited significantly higher serum transaminases, histological signs of necrosis, neutrophil infiltration, and serum levels of interleukin-6 compared to wild-type animals. Adoptive transfer of TRAIL-null NK cells into immunodeficient RAG2/common gamma-null mice was associated with significantly elevated liver damage compared to transfer of wild-type NK cells. In TRAIL-null mice, NK cells exhibit higher cytotoxicity and decreased differentiation compared to wild-type mice. In vitro, cytotoxicity against YAC-1 and secretion of interferon gamma by TRAIL-null NK cells were significantly increased compared to wild-type controls.

Conclusions
These experiments reveal that expression of TRAIL on NK cells is protective in a murine model of hepatic IRI through modulation of NK cell cytotoxicity and NK cell differentiation.

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ISO 690FAHRNER, René, Markus TROCHSLER, Nadia CORAZZA, Nadine GRAUBARDT, Adrian KEOGH, Daniel CANDINAS, Thomas BRUNNER, Deborah STROKA, Guido BELDI, 2014. Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand on NK Cells Protects From Hepatic Ischemia-Reperfusion Injury. In: Transplantation. 2014, 97(11), pp. 1102-1109. ISSN 0041-1337. eISSN 1534-6080. Available under: doi: 10.1097/TP.0000000000000101
BibTex
@article{Fahrner2014-06-15Tumor-28321,
  year={2014},
  doi={10.1097/TP.0000000000000101},
  title={Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand on NK Cells Protects From Hepatic Ischemia-Reperfusion Injury},
  number={11},
  volume={97},
  issn={0041-1337},
  journal={Transplantation},
  pages={1102--1109},
  author={Fahrner, René and Trochsler, Markus and Corazza, Nadia and Graubardt, Nadine and Keogh, Adrian and Candinas, Daniel and Brunner, Thomas and Stroka, Deborah and Beldi, Guido}
}
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    <dcterms:abstract xml:lang="eng">Background&lt;br /&gt;Ischemia-reperfusion injury (IRI) significantly contributes to graft dysfunction after liver transplantation. Natural killer (NK) cells are crucial innate effector cells in the liver and express tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), a potent inducer of hepatocyte cell death. Here, we investigated if TRAIL expression on NK cells contributes to hepatic IRI.&lt;br /&gt;&lt;br /&gt;Methods&lt;br /&gt;The outcome after partial hepatic IRI was assessed in TRAIL-null mice and contrasted to C57BL/6J wild-type mice and after NK cell adoptive transfer in RAG2/common gamma-null mice that lack T, B, and NK cells. Liver IRI was assessed by histological analysis, alanine aminotransferase, hepatic neutrophil activation by myeloperoxidase activity, and cytokine secretion at specific time points. NK cell cytotoxicity and differentiation were assessed in vivo and in vitro.&lt;br /&gt;&lt;br /&gt;Results&lt;br /&gt;Twenty-four hours after reperfusion, TRAIL-null mice exhibited significantly higher serum transaminases, histological signs of necrosis, neutrophil infiltration, and serum levels of interleukin-6 compared to wild-type animals. Adoptive transfer of TRAIL-null NK cells into immunodeficient RAG2/common gamma-null mice was associated with significantly elevated liver damage compared to transfer of wild-type NK cells. In TRAIL-null mice, NK cells exhibit higher cytotoxicity and decreased differentiation compared to wild-type mice. In vitro, cytotoxicity against YAC-1 and secretion of interferon gamma by TRAIL-null NK cells were significantly increased compared to wild-type controls.&lt;br /&gt;&lt;br /&gt;Conclusions&lt;br /&gt;These experiments reveal that expression of TRAIL on NK cells is protective in a murine model of hepatic IRI through modulation of NK cell cytotoxicity and NK cell differentiation.</dcterms:abstract>
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