Centre for Cancer Research, Monash Institute of Medical Research, Monash University, Clayton, Victoria, Australia.
Hum Mutat. 2010 Sep;31(9):1069-79. doi: 10.1002/humu.21321.
Human Toll-like receptors (TLRs) TLR7, TLR8, and TLR9 are important immune sensors of foreign nucleic acids encountered by phagocytes. Although there is growing evidence implicating TLR7 and TLR9 in the detection of intracellular pathogenic bacteria, characterization of such a role for TLR8 is currently lacking. A recent genetic study has correlated the presence of a TLR8 single nucleotide polymorphism (SNP) (rs3764880:A>G; p.Met1Val) with the development of active tuberculosis, suggesting a role for TLR8 in the detection of phagosomal bacteria. Here we provide the first direct evidence that TLR8 sensing is activated in human monocytic cells following Helicobacter pylori phagocytosis. In addition, we show that rs3764880 fine tunes translation of the two TLR8 main isoforms, without affecting protein function. Although we show that TLR8 variant 2 (TLR8v2) is the prevalent form of TLR8 contributing to TLR8 function, we also uncover a role for the TLR8 long isoform (TLR8v1) in the positive regulation of TLR8 function in CD16(+)CD14(+) differentiated monocytes. Thus, TLR8 sensing can be activated following bacterial phagocytosis, and rs3764880 may play a role in the modulation of TLR8-dependent microbicidal response of infected macrophages.
人类 Toll 样受体 (TLR) TLR7、TLR8 和 TLR9 是吞噬细胞遇到的外来核酸的重要免疫传感器。虽然越来越多的证据表明 TLR7 和 TLR9 参与了细胞内致病性细菌的检测，但 TLR8 的这种作用特征目前尚不清楚。最近的一项遗传研究表明，TLR8 单核苷酸多态性 (SNP)（rs3764880:A>G; p.Met1Val）的存在与活动性肺结核的发生相关，提示 TLR8 在吞噬体细菌的检测中发挥作用。在这里，我们首次提供了直接证据，表明 TLR8 感应在人单核细胞吞噬幽门螺杆菌后被激活。此外，我们还表明，rs3764880 微调了两种 TLR8 主要异构体的翻译，而不影响蛋白功能。尽管我们表明 TLR8 变体 2 (TLR8v2) 是对 TLR8 功能有贡献的 TLR8 主要形式，但我们还揭示了 TLR8 长型 (TLR8v1) 在 CD16(+)CD14(+)分化单核细胞中 TLR8 功能的正向调节中的作用。因此，TLR8 感应可以在细菌吞噬后被激活，rs3764880 可能在调节受感染巨噬细胞中 TLR8 依赖性杀菌反应中发挥作用。
