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乙醇诱导促炎细胞外囊泡的分泌，通过 G9a/GLP 表观遗传信号抑制成年海马神经发生。

Ethanol Induces Secretion of Proinflammatory Extracellular Vesicles That Inhibit Adult Hippocampal Neurogenesis Through G9a/GLP-Epigenetic Signaling.

机构信息

Bowles Center for Alcohol Studies, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC, United States.

Department of Pharmacology, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC, United States.

出版信息

Front Immunol. 2022 May 13;13:866073. doi: 10.3389/fimmu.2022.866073. eCollection 2022.

DOI:10.3389/fimmu.2022.866073
PMID:35634322
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9136051/
Abstract

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 or using 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.

摘要

成人海马神经发生（AHN）参与学习和记忆以及情绪调节。酗酒会减少 AHN，但其机制尚不清楚。神经发生龛中的小胶质细胞是 AHN 的重要调节者，而乙醇会促进促炎小胶质细胞的激活。我们最近报道，细胞外囊泡（EVs）介导了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丧失中的作用。在静息状态下，小胶质细胞通过分泌促神经发生的细胞外囊泡（pn-EVs）促进神经发生。使用集落刺激因子 1 受体（CSFR1）抑制剂或使用器官型脑片培养物（OBSC）耗尽小胶质细胞，分别导致齿状回的神经发生减少 30%和 56%，如双皮质素（DCX）免疫组化所示。同样，使用 CD68.hM4di 构建物对小胶质细胞进行化学遗传抑制导致 OBSC 中 77%的神经发生丧失，表明小胶质细胞具有促神经发生的静息表型。来自对照 OBSC 的 EVs 是促神经发生的（pn-EVs），当转移到其他未成熟的 OBSC 中时可增强神经发生，并恢复小胶质细胞耗竭培养物中的神经发生。乙醇抑制神经发生并导致促炎 EVs（EtOH-EVs）的分泌。EtOH-EVs 使未成熟的 OBSC 中的海马神经发生减少，其水平与乙醇相似。神经发生涉及染色质结构的复杂调节，这可能涉及 EV 信号转导。因此，发现 EtOH-EVs 富含 euchromatin histone lysine methyltransferase (Ehm2t/G9a) 的 mRNA，该酶通过组蛋白-3 赖氨酸-9 二甲基化（H3K9me2）降低染色质可及性。与 pn-EVs 相比，EtOH-EVs 在未成熟的 OBSC 中使 G9a 和 H3K9me2 增加了 2 倍。用 BIX-01294 或 UNC0642 抑制 G9a 的药理学抑制作用可防止 EtOH 和 EtOH-EVs 引起的神经发生丧失。因此，这项工作发现促炎 EtOH-EVs 通过 G9a 介导的染色质结构表观遗传修饰促进成年海马神经发生的丧失。

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