Adenosine A2A receptor activation reduces hepatic ischemia reperfusion injury by inhibiting CD1d-dependent NKT cell activation.
Adenosine A2A receptor activation reduces hepatic ischemia reperfusion injury by inhibiting CD1d-dependent NKT cell activation.
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DOI：
10.1084/jem.20061097
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发表时间：
2006-11-27
期刊：
影响因子：
--
通讯作者：
Linden J
中科院分区：
文献类型：
--
作者：
Lappas CM;Day YJ;Marshall MA;Engelhard VH;Linden J
缺血再灌注损伤源于缺血期间的组织损伤以及再灌注期间持续的炎症和损伤。通过淋巴细胞耗竭或使用选择性激动剂4 - {3-[6 - 氨基 - 9 - (5 - 乙基氨甲酰基 - 3,4 - 二羟基 - 四氢 - 呋喃 - 2 - 基)-9H - 嘌呤 - 2 - 基]- 丙 - 2 - 炔基}-环己烷羧酸甲酯（ATL146e）激活腺苷A2A受体（A2ARs）可减轻肝脏再灌注损伤。我们发现再灌注开始2小时后，NKT细胞受到刺激产生干扰素（IFN）-γ，并且使用抗体耗竭NK1.1阳性细胞（NK细胞和NKT细胞）或阻断CD1d介导的糖脂呈递给NKT细胞可重现ATL146e所提供的保护作用（通过血清丙氨酸氨基转移酶升高、组织学坏死、中性粒细胞积聚和血清IFN - γ升高来评估），但与ATL146e的保护作用并无累加效应。在RAG - 1基因敲除（KO）小鼠中观察到的再灌注损伤减轻现象，通过过继转移从野生型（WT）或A2AR KO小鼠（而非IFN - γ KO小鼠）中纯化的NKT细胞可恢复到野生型水平。此外，转移了A2AR - / - NKT细胞的动物不能通过ATL146e免受肝脏再灌注损伤。在体外，ATL146e强烈抑制抗CD3和α - 半乳糖神经酰胺触发的NKT细胞产生IFN - γ。这些发现表明肝脏再灌注损伤是由CD1d依赖性的NKT细胞激活引发的，并且这些细胞的激活受到A2AR激活的抑制。
Ischemia reperfusion injury results from tissue damage during ischemia and ongoing inflammation and injury during reperfusion. Liver reperfusion injury is reduced by lymphocyte depletion or activation of adenosine A2A receptors (A2ARs) with the selective agonist 4- {3-[6-amino-9-(5-ethylcarbamoyl-3,4-dihydroxy-tetrahydro-furan-2-yl)-9H-purin-2-yl]- prop-2-ynyl}-cyclohexanecarboxylic acid methyl ester (ATL146e). We show that NKT cells are stimulated to produce interferon (IFN)-γ by 2 h after the initiation of reperfusion, and the use of antibodies to deplete NK1.1-positive cells (NK and NKT) or to block CD1d-mediated glycolipid presentation to NKT cells replicates, but is not additive to, the protection afforded by ATL146e, as assessed by serum alanine aminotransferase elevation, histological necrosis, neutrophil accumulation, and serum IFN-γ elevation. Reduced reperfusion injury observed in RAG-1 knockout (KO) mice is restored to the wild-type (WT) level by adoptive transfer of NKT cells purified from WT or A2AR KO mice but not IFN-γ KO mice. Additionally, animals with transferred A2AR−/− NKT cells are not protected from hepatic reperfusion injury by ATL146e. In vitro, ATL146e potently inhibits both anti-CD3 and α-galactosylceramide–triggered production of IFN-γ by NKT cells. These findings suggest that hepatic reperfusion injury is initiated by the CD1d-dependent activation of NKT cells, and the activation of these cells is inhibited by A2AR activation.
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