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首页> 美国卫生研究院文献>American Journal of Physiology - Gastrointestinal and Liver Physiology >Preactivation of NKT cells with α-GalCer protects against hepatic ischemia-reperfusion injury in mouse by a mechanism involving IL-13 and adenosine A2A receptor
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Preactivation of NKT cells with α-GalCer protects against hepatic ischemia-reperfusion injury in mouse by a mechanism involving IL-13 and adenosine A2A receptor

机译：通过涉及IL-13和腺苷A2A受体的机制用α-GalCer预先激活NKT细胞可防止小鼠肝脏缺血再灌注损伤

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Hepatic preconditioning has emerged as a promising strategy of activating natural pathways to augment tolerance to liver ischemia-reperfusion (IR) injury. Liver-resident natural killer T (NKT) cells play an important role in modulating the local immune and inflammatory responses. This work was aimed to investigate whether preactivation of NKT cells could provide a beneficial “preconditioning” effect to ameliorate the subsequent hepatic IR injury. To selectively activate NKT cells, C57BL/6 mice were treated intraperitoneally with the glycolipid antigen α-galactosylceramide (α-GalCer) 1 h prior to hepatic ischemia. Significantly reduced liver IR injury was observed in mice pretreated with α- GalCer, and this protective effect was specifically abrogated by a CD1d blocking antibody. Serum TNF-α, IFN-γ, and IL-13 levels were markedly increased shortly after α-GalCer injection. Pretreatment with a neutralizing antibody against TNF-α or IFN-γ did not influence the protective effect of α-GalCer preconditioning, whereas preadministration of an IL-13 neutralizing antibody completely abolished the effect. Treatment with α-GalCer also led to an increased expression of adenosine A2A receptor (A2AR) in the liver, and blockade of A2AR by SH58261 diminished α-GalCer pretreatment-mediated attenuation of liver IR injury. In contrast, administration of the selective A2AR agonist reversed the counteracting effect of the IL-13 neutralizing antibody on α-GalCer preconditioning. Additionally, α-GalCer pretreatment was associated with a decreased neutrophil accumulation in the ischemic liver. These findings provide the first evidence that hepatic preconditioning by preactivation of NKT cells with α-GalCer protects the liver from IR injury via an IL-13 and adenosine A2AR-dependent mechanism.
机译：肝预处理已成为激活天然途径以增强对肝脏缺血再灌注（IR）损伤耐受性的一种有前途的策略。驻留肝脏的自然杀伤T（NKT）细胞在调节局部免疫和炎症反应中起重要作用。这项工作旨在研究NKT细胞的预激活是否可以提供有益的“预处理”效果，以减轻随后的肝IR损伤。为了选择性激活NKT细胞，在肝缺血前1小时用糖脂抗原α-半乳糖基神经酰胺（α-GalCer）腹膜内处理C57BL / 6小鼠。在用α-GalCer预处理的小鼠中观察到肝IR损伤显着降低，并且CD1d阻断抗体特异性消除了这种保护作用。注射α-GalCer后不久，血清TNF-α，IFN-γ和IL-13水平明显升高。用针对TNF-α或IFN-γ的中和抗体进行预处理不会影响α-GalCer预处理的保护作用，而预先给予IL-13中和抗体则完全消除了这种作用。用α-GalCer进行的治疗还导致肝脏中腺苷A2A受体（A2AR）的表达增加，SH58261对A2AR的阻断减少了α-GalCer预处理介导的肝IR损伤的减轻。相反，施用选择性A2AR激动剂可逆转IL-13中和抗体对α-GalCer预处理的抵消作用。另外，α-GalCer预处理与缺血性肝中嗜中性粒细胞积累减少有关。这些发现提供了第一个证据，即通过用α-GalCer预先激活NKT细胞进行肝预处理可通过IL-13和腺苷A2AR依赖性机制保护肝脏免受IR损伤。

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