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MicroRNA-146a protects against cognitive decline induced by surgical trauma by suppressing hippocampal neuroinflammation in mice

神经炎症 促炎细胞因子 海马结构 小胶质细胞 炎症 免疫印迹 海马体 医学 术后认知功能障碍 拮抗剂 免疫学 小RNA 认知 内科学 生物 精神科 生物化学 基因
作者
Lei Chen,Rui Dong,Yayuan Lu,Ying Zhou,Ke Li,Zongze Zhang,Mian Peng
出处
期刊:Brain Behavior and Immunity [Elsevier BV]
卷期号:78: 188-201 被引量:146
标识
DOI:10.1016/j.bbi.2019.01.020
摘要

Postoperative cognitive dysfunction (POCD) is a common postoperative complication that is associated with increased morbidity and mortality. However, the neuropathogenesis of this complication remains largely unknown. Neuroinflammation, in particular hippocampal inflammation, contributes to POCD. Recently, increasing evidence has supported the involvement of microRNAs (miRNAs) in the regulation of neuroinflammation in human neurological disorders. In the present study, we investigated the role of miR-146a, a key regulator of the innate immune response, in surgery-induced hippocampal inflammation and cognitive impairment. The expression of miR-146a was measured in BV-2 microglial cells stimulated with lipopolysaccharide (LPS) and hippocampal tissues of mice with POCD. Loss of function and overexpression studies were performed via transfection with miR-146a mimic/inhibitor in cultured BV-2 cell lines and intrahippocampal injection of miR-146a agomir/antagomir before surgery/anesthesia to identify the role of miR-146a in neuroinflammation and cognitive impairment. QPCR, Western blot and ELISA were used to determine the expression levels of downstream adaptor proteins and proinflammatory cytokines. Immunofluorescence staining was applied to evaluate the activation of microglia. Increased expression of miR-146a was observed in BV-2 microglial cells stimulated with LPS and hippocampal tissues of mice with POCD. Modulation of miR-146a expression via transfection of microglia with miR-146a mimic or inhibitor regulated the mRNA and protein expression levels of downstream targets of miR-146a (IRAK1 and TRAF6) as well as the release of proinflammatory cytokines (TNF-α, IL-1β and IL-6). In addition, overexpression of miR-146a attenuated hippocampus-dependent learning and memory impairment in mice with POCD, which was accompanied by decreased expression of the IRAK1/TRAF6/nuclear factor (NF)-κB pathway and downregulation of microglial activation in the hippocampus. Conversely, knockdown of miR-146a expression may exacerbate hippocampus-dependent learning and memory deficiency and hippocampal inflammation in mice with POCD. Collectively, our findings demonstrate the important role of miR-146a in the neuropathogenesis of POCD and suggest that miR-146a may be a potential therapeutic target for POCD.
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