TLR2 is constitutively expressed within the kidney and participates in ischemic renal injury through both MyD88-dependent and -independent pathways
TLR2 is constitutively expressed within the kidney and participates in ischemic renal injury through both MyD88-dependent and -independent pathways
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DOI：
10.4049/jimmunol.178.10.6252
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发表时间：
2007-05-15
影响因子：
4.4
通讯作者：
McKay, Dianne B.
中科院分区：
文献类型：
--
作者：
Shigeoka, Alana A.;Holscher, Todd D.;McKay, Dianne B.
TLR 是一个进化上保守的细胞膜蛋白家族，被认为在先天免疫和对组织损伤（包括缺血引起的组织损伤）的反应中发挥着重要作用。 TLR 信号通路通过两种近端接头蛋白 MyD88 或含有 Toll/IL-1R 结构域的接头诱导 IFN-β (Trif) 之一激活调节促生存蛋白以及促炎细胞因子和趋化因子表达的转录因子。我们的研究定义了人类和小鼠肾脏中 TLR2 的组成型蛋白表达，并深入了解 TLR2 缺陷可防止缺血性器官损伤的信号传导机制。我们的研究比较和对比了野生型小鼠和 TLR2、MyD88、Trif 和 MyD88 x Trif 缺陷小鼠的肾缺血影响。 TLR2 蛋白在肾脏的许多细胞类型中都很明显，包括髓质外带的肾小管、肾小球和肾脉管系统。人类和小鼠的蛋白质表达模式相似。 TLR2、MyD88 和 MyD88 x Trif 的缺失赋予了 24 小时时针对亚致死性缺血的生理学和组织学保护。有趣的是，TLR2 缺陷的小鼠比那些衔接蛋白 MyD88 缺陷的小鼠能更好地免受缺血性肾损伤，这提出了一种有趣的可能性，即 TLR-2 依赖性/MyD88 独立途径也导致肾损伤。我们得出结论，TLR2 蛋白在肾脏中组成型表达，并通过 MyD88 依赖性和 MyD88 独立途径发出信号，在急性缺血性损伤的发病机制中发挥重要作用。
TLRs are an evolutionarily conserved family of cell membrane proteins believed to play a significant role in innate immunity and the response to tissue injury, including that induced by ischemia. TLR signaling pathways activate transcription factors that regulate expression of prosurvival proteins, as well as proinflammatory cytokines and chemokines through one of two proximal adapter proteins, MyD88 or Toll/IL-1R domain-containing adaptor-inducing IFN-beta (Trif). Our study defines the constitutive protein expression of TLR2 in kidneys of humans and mice, and provides insight into the signaling mechanisms by which a deficiency of TLR2 protects from ischemic organ injury. Our study compared and contrasted the effects of renal ischemia in wild-type mice and mice deficient in TLR2, MyD88, Trif, and MyD88 x Trif. TLR2 protein was evident in many cell types in the kidney, including renal tubules of the outer stripe of the medulla, glomeruli, and in the renal vasculature. The pattern of protein expression was similar in humans and mice. The absence of TLR2, MyD88, and MyD88 x Trif conferred both physiologic and histologic protection against sublethal ischemia at 24 h. Interestingly, TLR2-deficient mice were better protected from ischemic renal injury than those deficient for the adapter protein MyD88, raising the intriguing possibility that TLR-2-dependent/MyD88-independent pathways also contribute to kidney injury. We conclude that TLR2 protein is constitutively expressed in the kidney and plays an important role in the pathogenesis of acute ischemic injury by signaling both MyD88-dependent and MyD88-independent pathways.