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
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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DOI：
10.1152/ajpgi.00041.2009
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发表时间：
2009-08-01
影响因子：
4.5
通讯作者：
Billiar, Timothy R.
中科院分区：
文献类型：
--
作者：
Cao, Zongxian;Yuan, Youzhong;Billiar, Timothy R.
曹Z，袁Y，Jeyabalan G，杜Q，Tsung A，Geller DA，Billiar TR。使用 α-GalCer 预激活 NKT 细胞可通过涉及 IL-13 和腺苷 A(2A) 受体的机制防止小鼠肝脏缺血再灌注损伤。 Am J Physiol Gastrointest Liver Physiol 297：G249-G258，2009。首次发表于 2009 年 6 月 25 日； doi: 10.1152/ajpgi.00041.2009.-肝脏预处理已成为一种有前途的激活自然途径以增强对肝脏缺血再灌注 (IR) 损伤耐受性的策略。肝脏驻留的自然杀伤 T (NKT) 细胞在调节局部免疫和炎症反应中发挥着重要作用。这项工作的目的是研究 NKT 细胞的预激活是否可以提供有益的“预处理”效应，以改善随后的肝 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-半乳糖苷神经酰胺 (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脏 IR 损伤显着减轻，并且这种保护作用被 CD1d 阻断抗体特异性消除。注射 α-GalCer 后不久，血清 TNF-α、IFN-γ 和 IL-13 水平显着升高。用针对TNF-α或IFN-γ的中和抗体进行预处理并不影响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该作用。 α-GalCer 治疗还导致肝脏中腺苷 A(2A) 受体 (A(2A)R) 的表达增加，并且 SH58261 对 A(2A)R 的阻断减少了 α-GalCer 预处理介导的肝脏 IR 损伤的减弱。相反，施用选择性 A(2A)R 激动剂 CGS21680 逆转了 IL-13 中和抗体对 α-GalCer 预处理的抵消作用。此外，α-GalCer 预处理与缺血肝脏中中性粒细胞积累的减少有关。这些发现提供了第一个证据，表明通过使用 α-GalCer 预激活 NKT 细胞进行肝脏预处理，可通过 IL-13 和腺苷 A(2A)R 依赖性机制保护肝脏免受 IR 损伤。
Cao Z, Yuan Y, Jeyabalan G, Du Q, Tsung A, Geller DA, Billiar TR. Preactivation of NKT cells with alpha-GalCer protects against hepatic ischemia-reperfusion injury in mouse by a mechanism involving IL-13 and adenosine A(2A) receptor. Am J Physiol Gastrointest Liver Physiol 297: G249-G258, 2009. First published June 25, 2009; doi: 10.1152/ajpgi.00041.2009.-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 alpha-galactosylceramide (alpha-GalCer) 1 h prior to hepatic ischemia. Significantly reduced liver IR injury was observed in mice pretreated with alpha-GalCer, and this protective effect was specifically abrogated by a CD1d blocking antibody. Serum TNF-alpha, IFN-gamma, and IL-13 levels were markedly increased shortly after alpha-GalCer injection. Pretreatment with a neutralizing antibody against TNF-alpha or IFN-gamma did not influence the protective effect of alpha-GalCer preconditioning, whereas preadministration of an IL-13 neutralizing antibody completely abolished the effect. Treatment with alpha-GalCer also led to an increased expression of adenosine A(2A) receptor (A(2A)R) in the liver, and blockade of A(2A)R by SH58261 diminished alpha-GalCer pretreatment-mediated attenuation of liver IR injury. In contrast, administration of the selective A(2A)R agonist CGS21680 reversed the counteracting effect of the IL-13 neutralizing antibody on alpha-GalCer preconditioning. Additionally, alpha-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 alpha-GalCer protects the liver from IR injury via an IL-13 and adenosine A(2A)R-dependent mechanism.