Genetic Modulation of TLR8 Response following Bacterial Phagocytosis
Genetic Modulation of TLR8 Response following Bacterial Phagocytosis
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DOI：
10.1002/humu.21321
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发表时间：
2010-09-01
期刊：
影响因子：
3.9
通讯作者：
Williams, Bryan R. G.
中科院分区：
文献类型：
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作者：
Gantier, Michael P.;Irving, Aaron T.;Williams, Bryan R. G.
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。尽管越来越多的证据表明 TLR7 和 TLR9 在细胞内致病菌的检测中发挥作用，但目前缺乏对 TLR8 这种作用的表征。最近的一项遗传学研究将 TLR8 单核苷酸多态性 (SNP) (rs3764880:A>G; p.Met1Val) 的存在与活动性结核病的发展相关联，表明 TLR8 在吞噬体细菌的检测中发挥作用。在这里，我们提供了第一个直接证据，证明 TLR8 传感在幽门螺杆菌吞噬后在人类单核细胞中被激活。此外，我们还发现 rs3764880 可以微调两个 TLR8 主要亚型的翻译，而不影响蛋白质功能。尽管我们表明TLR8变体2（TLR8v2）是TLR8促进TLR8功能的普遍形式，但我们还发现了TLR8长亚型（TLR8v1）在CD16（+）CD14（+）分化单核细胞中TLR8功能正向调节中的作用。因此，TLR8感应可以在细菌吞噬作用后被激活，并且rs3764880可能在受感染巨噬细胞的TLR8依赖性杀菌反应的调节中发挥作用。 Hum Mutat 31:1069-1079, 2010。(c) 2010 Wiley-Liss, Inc.
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. Hum Mutat 31:1069-1079, 2010. (c) 2010 Wiley-Liss, Inc.