Accelerated remyelination and immune modulation by the EBI2 agonist 7α,25-dihydroxycholesterol analogue in the cuprizone model

IF 6.9 2区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Biomedicine & Pharmacotherapy Pub Date : 2024-11-02 DOI:10.1016/j.biopha.2024.117653
{"title":"Accelerated remyelination and immune modulation by the EBI2 agonist 7α,25-dihydroxycholesterol analogue in the cuprizone model","authors":"","doi":"10.1016/j.biopha.2024.117653","DOIUrl":null,"url":null,"abstract":"<div><h3>Summary</h3><div>Research indicates a role for EBI2 receptor in remyelination, demonstrating that its deficiency or antagonism inhibits this process. However, activation of EBI2 with its endogenous ligand, oxysterol 7α,25-dihydroxycholesterol (7α,25OHC), does not enhance remyelination beyond the levels observed in spontaneously remyelinating tissue. We hypothesized that the short half-life of the natural ligand might explain this lack of beneficial effects and tested a synthetic analogue, CF<sub>3</sub>-7α,25OHC, in the cuprizone model. The data showed that extending the bioavailability of 7α,25OHC is sufficient to accelerate remyelination <em>in vivo</em>. Moreover, the analogue, in contrast to the endogenous ligand, upregulated brain expression of <em>Ebi2</em> and the synthesis of 15 lipids in the mouse corpus callosum. Mechanistically, the increased concentration of oxysterol likely disrupted its gradient in demyelinated areas of the brain, leading to the dispersion of infiltrating EBI2-expressing immune cells rather than their accumulation in demyelinated regions. Remarkably, the analogue CF<sub>3</sub>-7α,25OHC markedly decreased the lymphocyte and monocyte counts mimicking the key mechanism of action of some of the most effective disease-modifying therapies for multiple sclerosis. Furthermore, the <em>Cd4+</em> transcripts in the cerebellum and CD4+ cell number in the corpus callosum were reduced compared to vehicle-treated mice. These findings suggest a mechanism by which EBI2/7α,25OHC signalling modulates the immune response and accelerates remyelination <em>in vivo</em>.</div></div>","PeriodicalId":8966,"journal":{"name":"Biomedicine & Pharmacotherapy","volume":null,"pages":null},"PeriodicalIF":6.9000,"publicationDate":"2024-11-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Biomedicine & Pharmacotherapy","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S0753332224015397","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"MEDICINE, RESEARCH & EXPERIMENTAL","Score":null,"Total":0}
引用次数: 0

Abstract

Summary

Research indicates a role for EBI2 receptor in remyelination, demonstrating that its deficiency or antagonism inhibits this process. However, activation of EBI2 with its endogenous ligand, oxysterol 7α,25-dihydroxycholesterol (7α,25OHC), does not enhance remyelination beyond the levels observed in spontaneously remyelinating tissue. We hypothesized that the short half-life of the natural ligand might explain this lack of beneficial effects and tested a synthetic analogue, CF3-7α,25OHC, in the cuprizone model. The data showed that extending the bioavailability of 7α,25OHC is sufficient to accelerate remyelination in vivo. Moreover, the analogue, in contrast to the endogenous ligand, upregulated brain expression of Ebi2 and the synthesis of 15 lipids in the mouse corpus callosum. Mechanistically, the increased concentration of oxysterol likely disrupted its gradient in demyelinated areas of the brain, leading to the dispersion of infiltrating EBI2-expressing immune cells rather than their accumulation in demyelinated regions. Remarkably, the analogue CF3-7α,25OHC markedly decreased the lymphocyte and monocyte counts mimicking the key mechanism of action of some of the most effective disease-modifying therapies for multiple sclerosis. Furthermore, the Cd4+ transcripts in the cerebellum and CD4+ cell number in the corpus callosum were reduced compared to vehicle-treated mice. These findings suggest a mechanism by which EBI2/7α,25OHC signalling modulates the immune response and accelerates remyelination in vivo.
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
在铜绿素模型中,EBI2激动剂7α,25-二羟基胆固醇类似物可加速髓鞘再形成和免疫调节。
研究表明,EBI2 受体在再髓鞘化过程中发挥作用,证明其缺乏或拮抗会抑制这一过程。然而,用其内源性配体氧甾醇 7α,25-二羟基胆固醇(7α,25OHC)激活 EBI2,并不能增强髓鞘再形成,超过在自发性髓鞘再形成组织中观察到的水平。我们假设天然配体的半衰期较短可能是缺乏有益作用的原因,并在铜绿素模型中测试了合成类似物 CF3-7α,25OHC。数据显示,提高 7α,25OHC的生物利用率足以加速体内的再髓鞘化。此外,与内源性配体不同的是,该类似物能上调小鼠胼胝体中 Ebi2 的脑表达和 15 种脂类的合成。从机理上讲,氧杂环醇浓度的增加很可能破坏了其在大脑脱髓鞘区域的梯度,导致浸润的表达 EBI2 的免疫细胞分散,而不是聚集在脱髓鞘区域。值得注意的是,类似物CF3-7α,25OHC明显减少了淋巴细胞和单核细胞的数量,模仿了一些最有效的多发性硬化症疾病调节疗法的关键作用机制。此外,与用药物治疗的小鼠相比,小脑中的 Cd4+ 转录物和胼胝体中的 CD4+ 细胞数量也有所减少。这些研究结果表明,EBI2/7α,25OHC 信号调节免疫反应并加速体内再髓鞘化是一种机制。
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
CiteScore
11.90
自引率
2.70%
发文量
1621
审稿时长
48 days
期刊介绍: Biomedicine & Pharmacotherapy stands as a multidisciplinary journal, presenting a spectrum of original research reports, reviews, and communications in the realms of clinical and basic medicine, as well as pharmacology. The journal spans various fields, including Cancer, Nutriceutics, Neurodegenerative, Cardiac, and Infectious Diseases.
期刊最新文献
Molecular mechanism through which Tripterygium hypoglaucum (Lévl.) Hutch alleviates psoriasis ZenoSWATH DIA proteomics and clustering analysis of the effect of cysteamine at the cellular level in cystinotic fibroblasts Protective mechanism of Prim-O-glucosylcimifugin in the treatment of osteoarthritis: Based on lncRNA XIST regulation of Nav1.7 Mitochondria in skeletal system-related diseases Accelerated remyelination and immune modulation by the EBI2 agonist 7α,25-dihydroxycholesterol analogue in the cuprizone model
×
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