RORγt(+) IL-22-producing NKp46(+) cells protect from hepatic ischemia reperfusion injury in mice.
OBJECTIVE
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 (RORγt).


METHODS
To explore the role of NK22 cells in IRI in the absence of adaptive immunity, B6.RORγt-(gfp/wt)-reporter and B6.RORγt-(gfp/gfp)-knockout (KO) mice on a Rag KO background underwent 90min partial warm ischemia, followed by 24h of reperfusion.


RESULTS
Rag KO mice that possess fully functional NKp46(+) cells, and Rag-common-γ-chain-double-KO (Rag-γc-DKO) mice that lack T, B and NKp46(+) cells, were used as controls. We found that Rag-γc-DKO mice lacking NK22 cells show more severe levels of hepatocellular damage (GPT, histological injury) when compared to both Rag-RORγt-reporter and Rag KO mice that possess NK22 cells. Importantly, Rag-RORγt-reporter and Rag KO mice undergoing IRI expressed high protein levels of both IL-22 and GFP (RORγt), suggesting a protective role for RORγt(+) NK22 cells in IRI. Therefore, we tested the hypothesis that RORγt critically protects from IRI through the induction of hepatic NK22 cells by studying Rag-Rorγt-DKO mice under IRI conditions. We found that the lack of RORγt(+) NK22 cells in Rag-Rorγt-DKO mice significantly enhanced IR-induced hepatocellular injury, a phenotype that could be reversed upon adoptive transfer of Rag-Rorγt-reporter NK22 cells into DKO mice.


CONCLUSIONS
RORγt(+) NK22 cells play an important protective role in IRI in mice.
Department of Surgery, University Hospital Regensburg, Regensburg, Germany. Electronic address: elke.eggenhofer@ukr.de.
Elke
E
Eggenhofer
Department of Surgery, University Hospital Regensburg, Regensburg, Germany.
Manije
M
Sabet-Rashedi
Department of Surgery, University Hospital Regensburg, Regensburg, Germany.
Margareta
M
Lantow
Department of Surgery, University Hospital Regensburg, Regensburg, Germany.
Philipp
P
Renner
Department of Surgery, University Hospital Regensburg, Regensburg, Germany.
Jordi
J
Rovira
Department of Surgery, University Hospital Regensburg, Regensburg, Germany.
Gudrun E
GE
Koehl
Department of Surgery, University Hospital Regensburg, Regensburg, Germany.
Hans J
HJ
Schlitt
Department of Surgery, University Hospital Regensburg, Regensburg, Germany.
Edward K
EK
Geissler
Department of Surgery, University Hospital Regensburg, Regensburg, Germany; MedStar Georgetown Transplant Institute, Georgetown University Hospital, Washington, DC, USA. Electronic address: akroemer@me.com.
Alexander
A
Kroemer
D000818:Animals; D000950:Antigens, Ly / Q000032:analysis / Q000502:physiology*; D018398:Homeodomain Proteins / Q000502:physiology; D007371:Interferon-gamma / Q000096:biosynthesis; D007378:Interleukins / Q000096:biosynthesis*; D007694:Killer Cells, Natural / Q000502:physiology; D008099:Liver / Q000098:blood supply*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D055627:Natural Cytotoxicity Triggering Receptor 1 / Q000032:analysis / Q000502:physiology*; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3 / Q000032:analysis / Q000502:physiology*; D015427:Reperfusion Injury / Q000276:immunology / Q000517:prevention & control*; D000097043:Interleukin-22
D000950:Antigens, Ly; D018398:Homeodomain Proteins; D007371:Interferon-gamma; D007378:Interleukins; D055627:Natural Cytotoxicity Triggering Receptor 1; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3; D000097043:Interleukin-22; C118384:Ncr1 protein, mouse; C539901:Rorc protein, mouse; C064658:RAG-1 protein
IL-22; Liver injury; Liver transplantation; NK cells; RORγt