Abstract：
Toll-like receptor 8 (TLR8), an important innate immune receptor recognizing single stranded RNA and the antiviral imidazoquinoline compounds, can activate intracellular signaling pathway and produce an inflammatory response to kill and eliminate pathogens. However, the molecular regulation mechanisms of TLR8 signaling and its anti-infection activity are not fully elucidated. Our previous transcriptome analysis of porcine TLR8 (pTLR8) signaling suggested the immune checkpoint receptor TIM-3 as the potential regulator for pTLR8. Here we investigated TIM-3 in the regulation of pTLR8 signaling and its anti-infection activity. Our results showed that porcine TIM-3 is upregulated by pTLR8 signaling and TIM-3 inhibits pTLR8 signaling activity in a negative feedback way. Accordingly, TIM-3 disturbs pTLR8 mediated anti-bacterial and anti-viral activity. Mechanistically, TIM-3 suppresses PI3K-AKT pathway by inhibiting the TLR8-PI3K p85 interaction and subsequent AKT phosphorylation which is essential for TLR8 signaling and anti-infection activity. Therefore, our study reveals new insights into innate immune TLR8 signaling and its anti-infection function.
摘要：
Toll样受体8(TLR8),识别单链RNA和抗病毒咪唑喹啉化合物的重要先天性免疫受体，能激活细胞内信号通路,产生炎症反应,杀死和消除病原体。然而,TLR8信号的分子调控机制及其抗感染活性尚未完全阐明。我们先前对猪TLR8（pTLR8）信号传导的转录组分析提示免疫检查点受体TIM-3是pTLR8的潜在调节因子。在这里，我们研究了TIM-3对pTLR8信号传导的调控及其抗感染活性。我们的结果表明，猪TIM-3被pTLR8信号上调，TIM-3以负反馈方式抑制pTLR8信号活性。因此，TIM-3干扰pTLR8介导的抗菌和抗病毒活性。机械上,TIM-3通过抑制TLR8-PI3Kp85相互作用和随后的AKT磷酸化来抑制PI3K-AKT途径，这对于TLR8信号传导和抗感染活性至关重要。因此,我们的研究揭示了先天免疫TLR8信号及其抗感染功能的新见解。
