Shigeoka Alana A, Holscher Todd D, King Andrew J, Hall Frank W, Kiosses William B, Tobias Peter S, Mackman Nigel, McKay Dianne B
Department of Immunology, The Scripps Research Institute, La Jolla, CA 92037, USA.
J Immunol. 2007 May 15;178(10):6252-8. doi: 10.4049/jimmunol.178.10.6252.
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 MyD88xTrif. 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 MyD88xTrif 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.
Toll样受体（TLRs）是一类进化上保守的细胞膜蛋白家族，被认为在天然免疫以及对包括缺血诱导的组织损伤反应中发挥重要作用。TLR信号通路激活转录因子，这些转录因子通过两种近端衔接蛋白之一，即髓样分化因子88（MyD88）或含Toll/白细胞介素-1受体结构域的衔接蛋白诱导干扰素-β（Trif），来调节促生存蛋白以及促炎细胞因子和趋化因子的表达。我们的研究确定了人类和小鼠肾脏中TLR2的组成性蛋白表达，并深入了解了TLR2缺陷保护免受缺血性器官损伤的信号传导机制。我们的研究比较并对比了野生型小鼠以及TLR2、MyD88、Trif和MyD88xTrif缺陷小鼠肾缺血的影响。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、肾小球以及肾血管系统。人类和小鼠的蛋白表达模式相似。缺乏TLR2、MyD88和MyD88xTrif可在24小时对亚致死性缺血提供生理和组织学保护。有趣的是，TLR2缺陷小鼠比衔接蛋白MyD88缺陷小鼠更能免受缺血性肾损伤，这引发了一个有趣的可能性，即TLR-2依赖性/MyD88非依赖性途径也促成肾损伤。我们得出结论，TLR2蛋白在肾脏中组成性表达，并通过MyD88依赖性和MyD88非依赖性途径发出信号，在急性缺血性损伤的发病机制中起重要作用。
