Zusammenfassung
Background & Aims: NKp46(+) cells are major effector cells in the pathogenesis of hepatic ischemia reperfusion injury (IRI). Nevertheless, the precise role of unconventional subsets like the IL-22-producing NKp46(+) cells (NK22) remains unknown. The purpose of this study was to examine the role of NK22 cells in IRI in transplantation, particularly with respect to regulation by the transcription ...
Zusammenfassung
Background & Aims: NKp46(+) cells are major effector cells in the pathogenesis of hepatic ischemia reperfusion injury (IRI). Nevertheless, the precise role of unconventional subsets like the IL-22-producing NKp46(+) cells (NK22) remains unknown. The purpose of this study was to examine the role of NK22 cells in IRI in transplantation, particularly with respect to regulation by the transcription factor ROR-gamma-t (ROR gamma t). Methods: To explore the role of NK22 cells in IRI in the absence of adaptive immunity, B6.ROR gamma t-(gfp/wt)-reporter and B6.ROR gamma t-(gfp/gfp)-knockout (KO) mice on a Rag KO background underwent 90 min partial warm ischemia, followed by 24 h of reperfusion. Results: Rag KO mice that possess fully functional NKp46(+) cells, and Rag-common-gamma-chain-double-KO (Rag-gamma c-DKO) mice that lack T, B and NKp46(+) cells, were used as controls. We found that Rag-gamma c-DKO mice lacking NK22 cells show more severe levels of hepatocellular damage (GPT, histological injury) when compared to both Rag-ROR gamma t-reporter and Rag KO mice that possess NK22 cells. Importantly, Rag-ROR gamma t-reporter and Rag KO mice undergoing IRI expressed high protein levels of both IL-22 and GFP (ROR gamma t), suggesting a protective role for ROR gamma t(+) NK22 cells in IRI. Therefore, we tested the hypothesis that ROR gamma t critically protects from IRI through the induction of hepatic NK22 cells by studying Rag-Ror gamma t-DKO mice under IRI conditions. We found that the lack of ROR gamma t(+) NK22 cells in Rag-Ror gamma t-DKO mice significantly enhanced IR-induced hepatocellular injury, a phenotype that could be reversed upon adoptive transfer of Rag-Ror gamma t-reporter NK22 cells into DKO mice. Conclusions: ROR gamma t+ NK22 cells play an important protective role in IRI in mice. (C) 2015 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.
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