Division of Innate Immunity, Department of Microbiology and Immunology, Institute of Medical Science, University of Tokyo, Shirokanedai, Minato-ku, Tokyo, Japan.
Graduate School of Pharmaceutical Sciences, University of Tokyo, Hongo, Bunkyo-ku, Tokyo, Japan.
Int Immunol. 2018 Mar 8;30(2):43-51. doi: 10.1093/intimm/dxy016.
Nucleic acid (NA)-sensing Toll-like receptors (TLRs) respond to DNA/RNA derived from pathogens and dead cells. Structural studies have revealed a variety of molecular mechanisms by which TLRs sense NAs. Double-stranded RNA and single-stranded DNA directly bind to TLR3 and TLR9, respectively, whereas TLR7 and TLR8 bind to nucleosides and oligoribonucleotides derived from RNAs. Activation of ligand-bound TLRs is influenced by the functional status of TLRs. Proteolytic cleavage of NA-sensing TLRs enables ligand-dependent TLR dimerization. Trafficking of ligand-activated TLRs in endosomal and lysosomal compartments is requisite for production of type I interferons. Activation of NA-sensing TLRs is required for the control of viruses such as herpes simplex virus and endogenous retroviruses. On the other hand, excessive activation of NA-sensing TLRs drives disease progression in a variety of inflammatory diseases including systemic lupus erythematosus, heart failure, arthritis and non-alcoholic steatohepatitis. NA-sensing TLRs are targets for therapeutic intervention in these diseases. We here focus on our recent progresses in our understanding of NA-sensing TLRs.
核酸（NA）感应 Toll 样受体（TLRs）可识别病原体和死亡细胞产生的 DNA/RNA。结构研究揭示了 TLRs 感应 NAs 的多种分子机制。双链 RNA 和单链 DNA 分别直接与 TLR3 和 TLR9 结合，而 TLR7 和 TLR8 与 RNA 衍生的核苷和寡核糖核苷酸结合。配体结合的 TLR 的激活受 TLR 功能状态的影响。NA 感应 TLR 的蛋白水解切割使配体依赖性 TLR 二聚化成为可能。配体激活的 TLR 在内体和溶酶体区室中的运输对于 I 型干扰素的产生是必需的。NA 感应 TLR 的激活对于控制单纯疱疹病毒和内源性逆转录病毒等病毒是必需的。另一方面，NA 感应 TLR 的过度激活会导致多种炎症性疾病的疾病进展，包括系统性红斑狼疮、心力衰竭、关节炎和非酒精性脂肪性肝炎。NA 感应 TLR 是这些疾病治疗干预的靶点。我们在此重点介绍我们在理解 NA 感应 TLR 方面的最新进展。
