MicroRNA-138-5p Regulates Hippocampal Neuroinflammation and Cognitive Impairment by NLRP3/Caspase-1 Signaling Pathway in Rats.
MicroRNA-138-5p Regulates Hippocampal Neuroinflammation and Cognitive Impairment by NLRP3/Caspase-1 Signaling Pathway in Rats.
复制标题
MicroRNA-138-5p 通过 NLRP3/Caspase-1 信号通路调节大鼠海马神经炎症和认知障碍
DOI：
10.2147/jir.s304461
复制
发表时间：
2021
影响因子：
4.5
通讯作者：
Xu G
中科院分区：
文献类型：
--
作者：
Feng X;Hu J;Zhan F;Luo D;Hua F;Xu G
目的神经炎症是认知功能障碍发生和发展的重要致病因素。本研究旨在通过NLRP3/caspase-1信号通路探讨microRNA-138-5p(miR-138-5p)在大鼠海马神经炎症和认知功能障碍中的重要作用。材料与方法采用脑室注射(Icv)或脂多糖(LPS)刺激建立认知功能障碍大鼠模型和大鼠小胶质细胞炎症模型。用Morris水迷宫(MWM)和Y-迷宫测试评估大鼠的认知行为。采用实时定量聚合酶链式反应(qRT-PCR)、酶联免疫吸附试验(EL ISA)和免疫印迹分析(Western印迹)检测基因和蛋白的表达。通过生物信息学分析和双荧光素酶报告基因分析，验证了NLRP3与miR-138-5p的靶向关系。用苏木精-伊红(H&E)染色和免疫组织化学方法分别观察神经元形态和检测海马区阳性细胞。结果与对照组相比，内毒素组大鼠在MWM和Y迷宫实验中表现出明显的学习记忆障碍。NLRP3、Caspase-1和促炎细胞因子IL-1β和IL-18的表达上调，而miR-138-5p的表达下调。在认知障碍动物的微阵列数据中，miR-138-5p表达下调，并可以直接靶向NLRP3的3个ʹ-UTR区。此外，上调miR-138-5p可改善受损的认知功能，同时抑制海马神经炎症，表现为NLRP3/caspase-1轴表达减少，促炎细胞因子和小胶质细胞激活。本研究首次证实miR-138-5p抑制认知障碍大鼠海马区NLRP3/caspase-1信号通路的激活。结论脂多糖注射后miR-138-5p的低表达可能参与了NLRP3/caspase-1通路的激活，导致大鼠海马神经炎症和认知功能障碍。这些发现表明，这是治疗认知障碍的一条很有希望的途径。
Purpose Neuroinflammation is an essential causative factor in the pathogenesis and progression of cognitive impairment. The present study aims to evaluate the critical role of microRNA-138-5p (miR-138-5p) in hippocampal neuroinflammation and cognitive impairment through the NLRP3/caspase-1 signaling pathway in rats. Material and Methods We established the cognitive impairment rat model and RM (Rat microglia) microglial cellular inflammation model by intracerebroventricular (icv) injection or stimulation of lipopolysaccharide (LPS). Morris water maze (MWM) and Y-maze tests were performed to assess the cognitive behaviors. Quantitative real-time polymerase chain reaction (qRT-PCR), Enzyme-linked immune-sorbent assay (ELISA) and Western blot analysis were utilized to evaluate mRNA or protein expression. Bioinformatic analysis and dual-luciferase reporter gene assay were performed to verify the targeting relationship between NLRP3 and miR-138-5p. Besides, Hematoxylin and eosin (H&E) staining and immunohistochemistry were applied to observe the neuronal morphology and detect the positive cells of the hippocampus, respectively. Results Compared to the control groups, LPS-treated rats exhibited significantly impaired learning and memory in MWM and Y-maze tests. The expression of NLRP3, caspase-1 and pro-inflammation cytokines (IL-1β and IL-18) were upregulated, while miR-138-5p was downregulated both in rat hippocampus and RM cells treated with LPS. MiR-138-5p is downregulated in microarray data of cognitive impairment animals and could directly target the 3ʹ-UTR of NLRP3. Furthermore, upregulation of miR-138-5p improved impaired cognitive functions, while inhibited hippocampal neuroinflammation demonstrated by decreased expression of NLRP3/caspase-1 axis, pro-inflammation cytokines and microglial activation. This study demonstrates for the first time that miR-138-5p suppresses the hippocampal NLRP3/caspase-1 signaling pathway activation in cognition impaired rats. Conclusion The low expression of miR-138-5p after LPS administration may contribute to the activation of the NLRP3/caspase-1 pathway, leading to hippocampal neuroinflammation and cognitive impairment in rat models. These findings indicate a promising therapeutic avenue for cognitive disorders.