RORγt+ IL-22-producing NKp46+ cells protect from hepatic ischemia reperfusion injury in mice
RORγt+ IL-22-producing NKp46+ cells protect from hepatic ischemia reperfusion injury in mice
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DOI：
10.1016/j.jhep.2015.08.023
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发表时间：
2016-01-01
影响因子：
25.7
通讯作者：
Kroemer, Alexander
中科院分区：
文献类型：
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作者：
Eggenhofer, Elke;Sabet-Rashedi, Manije;Kroemer, Alexander
背景与目的：NKp46（+）细胞是肝脏缺血再灌注损伤（IRI）发生的主要效应细胞。然而，非常规亚群如产生il -22的NKp46（+）细胞（NK22）的确切作用仍然未知。本研究的目的是研究NK22细胞在移植IRI中的作用，特别是在转录因子ROR- γ -t （ROR γ -t）的调控方面。方法：探讨NK22细胞在缺乏适应性免疫（B6）的IRI中的作用。ROR γ t-(gfp/wt)-报告因子和B6。在Rag KO背景下，ROR γ t-(gfp/gfp)敲除（KO）小鼠进行90分钟局部热缺血，然后再灌注24小时。结果：以具有完全功能的NKp46（+）细胞的Rag- KO小鼠和缺乏T、B和NKp46（+）细胞的Rag- γ - c-DKO小鼠为对照。我们发现，与具有NK22细胞的Rag- ror γ t报告细胞小鼠和Rag- KO小鼠相比，缺乏NK22细胞的Rag-gamma c-DKO小鼠表现出更严重的肝细胞损伤（GPT，组织学损伤）。重要的是，发生IRI的Rag-ROR γ t报告细胞和Rag KO小鼠都表达了高水平的IL-22和GFP （ROR γ t）蛋白，这表明ROR γ t(+) NK22细胞在IRI中具有保护作用。因此，我们通过研究IRI条件下的Rag-Ror γ t- dko小鼠，验证了ROR γ t通过诱导肝脏NK22细胞对IRI起到关键保护作用的假设。我们发现，ragr - ROR γ t-DKO小鼠中ROR γ t(+) NK22细胞的缺乏显著增强了ir诱导的肝细胞损伤，这种表型可以在将ragr - ROR γ t报告细胞NK22细胞过继转移到DKO小鼠后逆转。结论：ROR γ t+ NK22细胞在小鼠IRI中起重要的保护作用。(C) 2015欧洲肝脏研究协会。Elsevier B.V.版权所有。
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.