Pro-neuroinflammatory and neurotoxic potential of extracellular histones H1 and H3

IF 2.4 4区 医学 Q3 NEUROSCIENCES Neuroscience Research Pub Date : 2024-01-24 DOI:10.1016/j.neures.2024.01.004
Seamus A. McRae , Christy M. Richards , Dylan E. Da Silva, Ishvin Riar, Sijie (Shirley) Yang, Noah E. Zurfluh, Julien Gibon, Andis Klegeris
{"title":"Pro-neuroinflammatory and neurotoxic potential of extracellular histones H1 and H3","authors":"Seamus A. McRae ,&nbsp;Christy M. Richards ,&nbsp;Dylan E. Da Silva,&nbsp;Ishvin Riar,&nbsp;Sijie (Shirley) Yang,&nbsp;Noah E. Zurfluh,&nbsp;Julien Gibon,&nbsp;Andis Klegeris","doi":"10.1016/j.neures.2024.01.004","DOIUrl":null,"url":null,"abstract":"<div><p>Histones organize DNA within cellular nuclei, but they can be released from damaged cells. In peripheral tissues extracellular histones act as damage-associated molecular patterns (DAMPs) inducing pro-inflammatory activation of immune cells. Limited studies have considered DAMP-like activity of histones in the central nervous system (CNS); therefore, we studied the effects of extracellular histones on microglia, the CNS immunocytes, and on neuronal cells. Both the linker histone H1 and the core histone H3 induced pro-inflammatory activation of microglia-like cells by upregulating their secretion of NO and cytokines, including interferon-γ-inducible protein 10 (IP-10) and tumor necrosis factor-α (TNF). The selective inhibitors MMG-11 and TAK-242 were used to demonstrate involvement of toll-like receptors (TLR) 2 and 4, respectively, in H1-induced NO secretion by BV-2 microglia. H1, but not H3, downregulated the phagocytic activity of BV-2 microglia. H1 was also directly toxic to all neuronal cell types studied. We conclude that H1, and to a lesser extent H3, when released extracellularly, have the potential to act as a CNS DAMPs. Inhibition of the DAMP-like effects of extracellular histones on microglia and their neurotoxic activity represents a potential strategy for combating neurodegenerative diseases that are characterized by the adverse activation of microglia and neuronal death.</p></div>","PeriodicalId":19146,"journal":{"name":"Neuroscience Research","volume":"204 ","pages":"Pages 34-45"},"PeriodicalIF":2.4000,"publicationDate":"2024-01-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0168010224000087/pdfft?md5=a0f020e724e7e3d8ac93459e30a6ea40&pid=1-s2.0-S0168010224000087-main.pdf","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Neuroscience Research","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S0168010224000087","RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q3","JCRName":"NEUROSCIENCES","Score":null,"Total":0}
引用次数: 0

Abstract

Histones organize DNA within cellular nuclei, but they can be released from damaged cells. In peripheral tissues extracellular histones act as damage-associated molecular patterns (DAMPs) inducing pro-inflammatory activation of immune cells. Limited studies have considered DAMP-like activity of histones in the central nervous system (CNS); therefore, we studied the effects of extracellular histones on microglia, the CNS immunocytes, and on neuronal cells. Both the linker histone H1 and the core histone H3 induced pro-inflammatory activation of microglia-like cells by upregulating their secretion of NO and cytokines, including interferon-γ-inducible protein 10 (IP-10) and tumor necrosis factor-α (TNF). The selective inhibitors MMG-11 and TAK-242 were used to demonstrate involvement of toll-like receptors (TLR) 2 and 4, respectively, in H1-induced NO secretion by BV-2 microglia. H1, but not H3, downregulated the phagocytic activity of BV-2 microglia. H1 was also directly toxic to all neuronal cell types studied. We conclude that H1, and to a lesser extent H3, when released extracellularly, have the potential to act as a CNS DAMPs. Inhibition of the DAMP-like effects of extracellular histones on microglia and their neurotoxic activity represents a potential strategy for combating neurodegenerative diseases that are characterized by the adverse activation of microglia and neuronal death.

查看原文
分享 分享
微信好友 朋友圈 QQ好友 复制链接
本刊更多论文
细胞外组蛋白 H1 和 H3 的促神经炎症和神经毒性潜力
组蛋白在细胞核内组织 DNA,但也会从受损细胞中释放出来。在外周组织中,细胞外组蛋白可作为损伤相关分子模式(DAMPs)诱导免疫细胞的促炎激活。对组蛋白在中枢神经系统(CNS)中的 DAMP 类活性的研究有限;因此,我们研究了细胞外组蛋白对小胶质细胞、中枢神经系统免疫细胞和神经元细胞的影响。连接组蛋白 H1 和核心组蛋白 H3 通过上调小胶质细胞 NO 和细胞因子(包括干扰素-γ 诱导蛋白 10(IP-10)和肿瘤坏死因子-α(TNF))的分泌,诱导小胶质细胞的促炎激活。选择性抑制剂 MMG-11 和 TAK-242 被用来证明收费样受体(TLR)2 和 4 分别参与了 H1 诱导 BV-2 小胶质细胞分泌 NO 的过程。H1 而非 H3 能降低 BV-2 小胶质细胞的吞噬活性。H1 还对研究的所有神经细胞类型具有直接毒性。我们得出的结论是,H1(其次是 H3)在细胞外释放时有可能成为中枢神经系统的 DAMPs。抑制细胞外组蛋白对小胶质细胞的 DAMP 样效应及其神经毒性活性,是防治以小胶质细胞不良激活和神经元死亡为特征的神经退行性疾病的一种潜在策略。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
求助全文
约1分钟内获得全文 去求助
来源期刊
Neuroscience Research
Neuroscience Research 医学-神经科学
CiteScore
5.60
自引率
3.40%
发文量
136
审稿时长
28 days
期刊介绍: The international journal publishing original full-length research articles, short communications, technical notes, and reviews on all aspects of neuroscience Neuroscience Research is an international journal for high quality articles in all branches of neuroscience, from the molecular to the behavioral levels. The journal is published in collaboration with the Japan Neuroscience Society and is open to all contributors in the world.
期刊最新文献
LRP1-mediated p-tau propagation contributes to cognitive impairment after chronic neuropathic pain in rats. Stress and parental behaviors. Spatial dynamics of spontaneous activity in the developing and adult cortices. Detailed analysis of drift diffusion model parameters estimated for the ultimatum game. Cell type census in cerebral cortex reveals species-specific brain function and connectivity.
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
现在去查看 取消
×
提示
确定
0
微信
客服QQ
Book学术公众号 扫码关注我们
反馈
×
意见反馈
请填写您的意见或建议
请填写您的手机或邮箱
已复制链接
已复制链接
快去分享给好友吧!
我知道了
×
扫码分享
扫码分享
Book学术官方微信
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术
文献互助 智能选刊 最新文献 互助须知 联系我们:info@booksci.cn
Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。
Copyright © 2023 Book学术 All rights reserved.
ghs 京公网安备 11010802042870号 京ICP备2023020795号-1