Guanosine and its modified derivatives are endogenous ligands for TLR7.
Guanosine and its modified derivatives are endogenous ligands for TLR7.
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DOI：
10.1093/intimm/dxv062
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发表时间：
2016-05
影响因子：
4.4
通讯作者：
Takuma Shibata;U. Ohto;S. Nomura;K. Kibata;Y. Motoi;Yan Zhang;Y. Murakami;Ryutaro Fukui;T. Ishimot
中科院分区：
文献类型：
--
作者：
Takuma Shibata;U. Ohto;S. Nomura;K. Kibata;Y. Motoi;Yan Zhang;Y. Murakami;Ryutaro Fukui;T. Ishimot
Toll样受体(TLR7)和Toll样受体(TLR8)被认为是识别病毒单链RNA的分子。虽然这些受体也对合成的小化学配体如CL075和R848产生反应，但这些受体是否能感知天然小分子仍有待确定。在人TLR8(HuTLR8)与单链RNA结合的结构中，存在两个配体结合部位：一个与尿苷结合，另一个与寡核苷酸结合。这一发现表明huTLR8识别单链RNA的降解产物，这表明存在天然的小配体。我们发现在ORN存在的情况下，TLR7可以作为鸟苷(G)/2‘-脱氧鸟苷(DG)的传感器，而ORN可以加强TLR7与G/DG的相互作用。此外，7-甲基鸟苷、8-羟基鸟苷(8-OHG)和8-羟基脱氧鸟苷(8-OHdG)等修饰核苷可激活ONS激活TLR7。重要的是，8-OHdG-一种功能未知的众所周知的DNA氧化损伤标记物-在小鼠和人类免疫细胞中都能诱导与G和DG相当的强大细胞因子的产生。虽然8-OHdG与TLR7/ORN结合的亲和力低于DG，但在等温滴定热法中，8-OHdG在血清中的代谢比DG更稳定，这表明8-OHdG在体内作为内源性配体作用于TLR7，以解决G类似物在疾病状态中的作用。我们还研究了遭受TLR7依赖的全身炎症的Unc93b1(D34A/D34A)小鼠的巨噬细胞，发现Unc93b1(D34A/D34A)巨噬细胞对单独或8-OHdG与ORN的反应显著增强。综上所述，我们的结果为G、DG、8-OHG和8-OHdG是TLR7的新的内源性配体提供了证据。
Toll-like receptor (TLR) 7and 8 were considered to recognize single-strand RNA (ssRNA) from viruses. Although these receptors also respond to synthetic small chemical ligands, such as CL075 and R848, it remains to be determined whether these receptors sense natural small molecules or not. In the structure of human TLR8 (huTLR8) with ssRNA, there are two ligand-binding sites: one binds a uridine and the other binds an oligoribonucleotide (ORN). This finding demonstrates that huTLR8 recognizes degradation products of ssRNA, suggesting the presence of natural small ligands. We here show that TLR7 works as the sensor for guanosine (G)/2'-deoxyguanosine (dG) in the presence of ORN where ORN strengthens TLR7 interaction with G/dG. In addition, modified nucleosides such as 7-methylguanosine, 8-hydroxyguanosine (8-OHG) and 8-hydroxydeoxyguanosine (8-OHdG) activated TLR7 with ORNs. Importantly, 8-OHdG-a well-known oxidative DNA damage marker with unknown function-induced strong cytokine production comparable to G and dG both in mouse and human immune cells. Although 8-OHdG bound TLR7/ORN with lower affinity than dG did in isothermal titration calorimetry, administered 8-OHdG was metabolically more stable than dG in the serum, indicating that 8-OHdG acts on TLR7 as an endogenous ligand in vivo To address a role of G analogs in the disease state, we also examined macrophages from Unc93b1 (D34A/D34A) mice, which suffer from TLR7-dependent systemic inflammation, and found that Unc93b1 (D34A/D34A) macrophages showed significantly enhanced response to G alone or 8-OHdG with ORN. In conclusion, our results provide evidence that G, dG, 8-OHG and 8-OHdG are novel endogenous ligands for TLR7.