Coleman Leon G, Zou Jian, Crews Fulton T
Bowles Center for Alcohol Studies, The University of North Carolina School of Medicine, 104 Manning Drive, 1007 Thurston-Bowles Building, CB# 7178 UNC-CH, Chapel Hill, NC, 27599, USA.
Bowles Center for Alcohol Studies, University of North Carolina at Chapel Hill, 104 Manning Drive, CB#7178, Thurston-Bowles Building Room 1007, Chapel Hill, NC, 27599, USA.
J Neuroinflammation. 2017 Jan 25;14(1):22. doi: 10.1186/s12974-017-0799-4.
Toll-like receptor (TLR) signaling is emerging as an important component of neurodegeneration. TLR7 senses viral RNA and certain endogenous miRNAs to initiate innate immune responses leading to neurodegeneration. Alcoholism is associated with hippocampal degeneration, with preclinical studies linking ethanol-induced neurodegeneration with central innate immune induction and TLR activation. The endogenous miRNA let-7b binds TLR7 to cause neurodegeneration.
TLR7 and other immune markers were assessed in postmortem human hippocampal tissue that was obtained from the New South Wales Tissue Bank. Rat hippocampal-entorhinal cortex (HEC) slice culture was used to assess specific effects of ethanol on TLR7, let-7b, and microvesicles.
We report here that hippocampal tissue from postmortem human alcoholic brains shows increased expression of TLR7 and increased microglial activation. Using HEC slice culture, we found that ethanol induces TLR7 and let-7b expression. Ethanol caused TLR7-associated neuroimmune gene induction and initiated the release let-7b in microvesicles (MVs), enhancing TLR7-mediated neurotoxicity. Further, ethanol increased let-7b binding to the danger signaling molecule high mobility group box-1 (HMGB1) in MVs, while reducing let-7 binding to classical chaperone protein argonaute (Ago2). Flow cytometric analysis of MVs from HEC media and analysis of MVs from brain cell culture lines found that microglia were the primary source of let-7b and HMGB1-containing MVs.
Our results identify that ethanol induces neuroimmune pathology involving the release of let-7b/HMGB1 complexes in microglia-derived microvesicles. This contributes to hippocampal neurodegeneration and may play a role in the pathology of alcoholism.
Toll样受体（TLR）信号传导正逐渐成为神经退行性变的一个重要组成部分。TLR7可识别病毒RNA和某些内源性微小RNA（miRNA），从而启动导致神经退行性变的先天性免疫反应。酒精中毒与海马体退化有关，临床前研究将乙醇诱导的神经退行性变与中枢先天性免疫诱导及TLR激活联系起来。内源性miRNA let-7b可与TLR7结合导致神经退行性变。
对从新南威尔士州组织库获取的人类海马体尸检组织中的TLR7及其他免疫标志物进行评估。采用大鼠海马-内嗅皮质（HEC）切片培养来评估乙醇对TLR7、let-7b和微泡的特定影响。
我们在此报告，人类酒精中毒者尸检脑的海马体组织显示TLR7表达增加，小胶质细胞激活增强。利用HEC切片培养，我们发现乙醇可诱导TLR7和let-7b表达。乙醇导致与TLR7相关的神经免疫基因诱导，并引发微泡（MVs）中let-7b的释放，增强TLR7介导的神经毒性。此外，乙醇增加了MVs中let-7b与危险信号分子高迁移率族蛋白B1（HMGB1）的结合，同时减少了let-7与经典伴侣蛋白AGO2的结合。对HEC培养基中的MVs进行流式细胞术分析以及对脑细胞系中的MVs进行分析发现，小胶质细胞是let-7b和含HMGB1的MVs的主要来源。
我们的结果表明，乙醇可诱导涉及小胶质细胞来源的微泡中let-7b/HMGB1复合物释放的神经免疫病理学改变。这会导致海马体神经退行性变，并可能在酒精中毒的病理过程中发挥作用。
