Ethanol Induces Secretion of Proinflammatory Extracellular Vesicles That Inhibit Adult Hippocampal Neurogenesis Through G9a/GLP-Epigenetic Signaling.
Ethanol Induces Secretion of Proinflammatory Extracellular Vesicles That Inhibit Adult Hippocampal Neurogenesis Through G9a/GLP-Epigenetic Signaling.
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DOI：
10.3389/fimmu.2022.866073
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发表时间：
2022
影响因子：
7.3
通讯作者：
中科院分区：
文献类型：
--
作者：
成人海马区神经发生与学习记忆和情绪调节有关。暴饮暴食的乙醇会降低血管紧张素转换酶的活性，但其机制尚不清楚。神经源性小胶质细胞是AHN的重要调节因子，乙醇可促进促炎小胶质细胞的激活。我们最近报道了细胞外小泡(EVS)介导乙醇诱导的小胶质细胞炎症信号转导。因此，我们研究了EVS在乙醇诱导的成年海马神经发生缺失中的作用。静息状态下，小胶质细胞通过分泌前神经源性胞外小泡(pn-EV)促进神经发生。用克隆刺激因子1受体(CSFR1)抑制在体内或使用体外器官型脑片培养(OBSCs)去除小胶质细胞分别导致30%和56%的海马齿状体内神经发生的损失，根据双皮质激素(DCX)的免疫组织化学检测。同样，使用CD68.hM4di结构抑制小胶质细胞的化学发生会导致OBSC中77%的损失，这表明了一种支持神经源性的静息小胶质细胞表型。来自对照OBSC的EV是前神经源性的(pn-EVS)，当转移到其他幼稚的OBSC时，促进了神经发生，并在小胶质细胞耗尽的培养中恢复了神经发生。乙醇抑制神经发生并引起促炎性血管内皮细胞(EtoH-EVS)的分泌。Etoh-EVS以与乙醇相似的水平减少幼稚OBSC的海马神经发生。神经发生涉及染色质结构的复杂调节，可能涉及EV信号。因此，Etoh-Evs被发现富含常染色素组蛋白赖氨酸甲基转移酶(Ehm2t/G9a)的mRNA，该酶通过组蛋白-3赖氨酸-9二甲基化(H3K9me2)减少染色质的可及性。Etoh-EVS对幼稚OBSCs的G9a和H3K9me2的诱导作用是pn-EVS的2倍。BIX-01294或UNC0642对G9a的药理抑制可阻止EtoH和Etoh-EVS引起的神经再生丧失。因此，这项工作发现，促炎性Etoh-Evs通过G9a介导的染色质结构的表观遗传修饰促进成年海马神经发生的丧失。
Adult hippocampal neurogenesis (AHN) is involved in learning and memory as well as regulation of mood. Binge ethanol reduces AHN, though the mechanism is unknown. Microglia in the neurogenic niche are important regulators of AHN, and ethanol promotes proinflammatory microglia activation. We recently reported that extracellular vesicles (EVs) mediate ethanol-induced inflammatory signaling in microglia. Therefore, we investigated the role of EVs in ethanol-induced loss of adult hippocampal neurogenesis. At rest, microglia promoted neurogenesis through the secretion of pro-neurogenic extracellular vesicles (pn-EVs). Depletion of microglia using colony-stimulating factor 1 receptor (CSFR1) inhibition in vivo or using ex vivo organotypic brain slice cultures (OBSCs) caused a 30% and 56% loss of neurogenesis in the dentate, respectively, as measured by immunohistochemistry for doublecortin (DCX). Likewise, chemogenetic inhibition of microglia using a CD68.hM4di construct caused a 77% loss in OBSC, indicating a pro-neurogenic resting microglial phenotype. EVs from control OBSC were pro-neurogenic (pn-EVs), enhancing neurogenesis when transferred to other naive OBSC and restoring neurogenesis in microglia-depleted cultures. Ethanol inhibited neurogenesis and caused secretion of proinflammatory EVs (EtOH-EVs). EtOH-EVs reduced hippocampal neurogenesis in naïve OBSC by levels similar to ethanol. Neurogenesis involves complex regulation of chromatin structure that could involve EV signaling. Accordingly, EtOH-EVs were found to be enriched with mRNA for the euchromatin histone lysine methyltransferase (Ehm2t/G9a), an enzyme that reduces chromatin accessibility through histone-3 lysine-9 di-methylation (H3K9me2). EtOH-EVs induced G9a and H3K9me2 by 2-fold relative to pn-EVs in naïve OBSCs. Pharmacological inhibition of G9a with either BIX-01294 or UNC0642 prevented loss of neurogenesis caused by both EtOH and EtOH-EVs. Thus, this work finds that proinflammatory EtOH-EVs promote the loss of adult hippocampal neurogenesis through G9a-mediated epigenetic modification of chromatin structure.
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影响因子：
3.5
作者：
Di Liegro CM;Schiera G;Di Liegro I
通讯作者：
Di Liegro I
DOI：
10.1016/j.pnpbp.2014.05.003
发表时间：
2014-10-03
影响因子：
5.6
作者：
Geil, Chelsea R.;Hayes, Dayna M.;McClain, Justin A.;Liput, Daniel J.;Marshall, S. Alex;Chen, Kevin Y.;Nixon, Kimberly
通讯作者：
Nixon, Kimberly
影响因子：
10.6
作者：
Crews, Fulton T.;Qin, Liya;Sheedy, Donna;Vetreno, Ryan P.;Zou, Jian
通讯作者：
Zou, Jian
影响因子：
2.9
作者：
Broadwater MA;Liu W;Crews FT;Spear LP
通讯作者：
Spear LP
影响因子：
4.3
作者：
Desai, Chirag S.;Khan, Aisha;Maile, Robert
通讯作者：
Maile, Robert