Extracellular RNAs-TLR3 signaling contributes to cognitive decline in a mouse model of postoperative cognitive dysfunction
Extracellular RNAs-TLR3 signaling contributes to cognitive decline in a mouse model of postoperative cognitive dysfunction
复制标题
细胞外 RNAs-TLR3 信号传导导致术后认知功能障碍小鼠模型认知能力下降
DOI：
10.1016/j.bbi.2019.04.024
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发表时间：
2019-08-01
影响因子：
15.1
通讯作者：
Liu, Jin
中科院分区：
文献类型：
--
作者：
Chen, Chan;Gao, Rui;Liu, Jin
术后认知功能障碍（POCD）被认为是老年患者手术后的严重并发症。toll样受体3 （TLR3）最近被报道在海马体依赖的工作记忆中起重要作用。然而，TLR3在POCD发展中的作用尚不清楚。在本研究中，我们假设麻醉和手术过程中增加的细胞外rna (exRNAs)，特别是双链rna （dsRNAs）会激活TLR3信号通路并介导POCD。使用小鼠POCD模型，20-22月龄野生型（WT）小鼠接受单侧肾切除术，与假手术组相比，手术组TLR3表达水平升高，神经元和小胶质细胞共定位。与WT小鼠相比，TLR3敲除（KO,(-/-)）小鼠海马依赖性记忆得到改善，炎症细胞因子的产生和细胞凋亡减少。在体外和体内模型中均发现增加的exRNAs和/或与TLR3共定位。值得注意的是，TLR3/dsRNA复合物抑制剂降低了海马dsRNA水平和TLR3表达，减轻了海马炎症细胞因子的产生和凋亡，从而改善了海马依赖性记忆。我们的研究结果表明，应激条件下存在的exrna，特别是dsRNAs，可能触发TLR3激活，启动下游炎症和凋亡信号，并在POCD的发展中发挥重要作用。
Postoperative cognitive dysfunction (POCD) is considered a severe complication after surgery among elderly patients. Toll-like receptor 3 (TLR3) has recently been reported to play an important role in hippocampus-dependent working memory. However, the role of TLR3 in the development of POCD remains unclear. In the current study, we hypothesized that increased extracellular RNAs (exRNAs) during anesthesia and surgical operation, especially double stranded RNAs (dsRNAs), would activate TLR3 signaling pathways and mediate POCD. Using a mouse model of POCD, 20-22 months wild-type (WT) mice were undergoing unilateral nephrectomy and increased TLR3 expression levels and co-localization with neuronal and microglial cells were found in the surgery group compared with the sham group. Compared with WT mice, TLR3 knockout (KO, (-/-)) mice had improved hippocampus-dependent memory and attenuated production of inflammatory cytokines and apoptosis. Increased exRNAs and/or co-localization with TLR3 were found in both in vitro and in vivo models. Of note, TLR3/dsRNA complex inhibitor administration reduced hippocampal dsRNA level and TLR3 expression, attenuated hippocampal inflammatory cytokines production and apoptosis, and thus improved hippocampus-dependent memory. Our results indicate that exRNAs, especially dsRNAs, present under stressful conditions may trigger TLR3 activation and initiate the downstream inflammatory and apoptotic signaling, and play a substantial role in the development of POCD.