Cutting edge: TLR4 activation mediates liver ischemia/reperfusion inflammatory response via IFN regulatory factor 3-dependent MyD88-independent pathway
Cutting edge: TLR4 activation mediates liver ischemia/reperfusion inflammatory response via IFN regulatory factor 3-dependent MyD88-independent pathway
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DOI：
10.4049/jimmunol.173.12.7115
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发表时间：
2004-12-15
影响因子：
4.4
通讯作者：
Kupiec-Weglinski, JW
中科院分区：
文献类型：
--
作者：
Zhai, Y;Shen, XD;Kupiec-Weglinski, JW
缺血再灌注损伤（IRI）在临床环境中会导致过度且有害的炎症反应，其触发分子机制仍不清楚。本研究分析了 TLR 系统在已建立的小鼠肝脏热缺血再灌注模型中的作用。通过将 TLR 敲除小鼠与野生型小鼠进行平行比较，我们发现 TLR4 而不是 TLR2 在启动 IRI 级联反应中是特别需要的，如肝功能（血清丙氨酸转氨酶水平）、病理学和促炎细胞因子/趋化因子（TNF-α、IL-6、 干扰素诱导蛋白 10)。然后我们研究了 TLR4 激活的下游信号通路。我们的结果表明，IFN 调节因子 3（而非 MyD88）介导 IRI 诱导的 TLR4 激活，导致肝脏炎症和肝细胞损伤。本研究记录了 TLR 在临床相关非感染性疾病模型中的选择性使用，并确定了肝脏 IRI 病理生理学的触发分子机制。
The triggering molecular mechanism of ischemia-reperfusion injury (IRI), which in clinical settings results in excessive and detrimental inflammatory responses, remains unclear. This study analyzes the role of the TLR system in an established murine model of liver warm ischemia followed by reperfusion. By contrasting in parallel TLR knockout mice with their wild-type counterparts, we found that TLR4, but not TLR2, was specifically required in initiating the IRI cascade, as manifested by liver function (serum alanine aminotransferase levels), pathology, and local induction of proinflammatory cytokines/chemokines (TNF-alpha, IL-6, IFN-inducible protein 10). We then investigated the downstream signaling pathway of TLR4 activation. Our results show that IFN regulatory factor 3, but not MyD88, mediated IRI-induced TLR4 activation leading to liver inflammation and hepatocellular damage. This study documents the selective usage of TLR in a clinically relevant noninfectious disease model, and identifies a triggering molecular mechanism in the pathophysiology of liver IRI.