HO-1 represses NF-κB signaling pathway to mediate microglia polarization and phagocytosis in intracerebral hemorrhage.

IF 2.9 3区 医学 Q2 NEUROSCIENCES
Weiping Chen, Zhiping Wu, Zhijuan Cheng, Yangbo Zhang, Qinghua Luo, Min Yin
{"title":"HO-1 represses NF-κB signaling pathway to mediate microglia polarization and phagocytosis in intracerebral hemorrhage.","authors":"Weiping Chen, Zhiping Wu, Zhijuan Cheng, Yangbo Zhang, Qinghua Luo, Min Yin","doi":"10.1016/j.neuroscience.2024.12.020","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>Microglia polarization plays a crucial role in inflammatory injury of brain following intracerebral hemorrhage (ICH). Heme oxygenase-1 (HO-1) has demonstrated protective properties against inflammation and promote hematoma clearance after ICH. The objective of this study was to explore impacts of HO-1 on microglia polarization and phagocytosis after ICH, along with the underlying mechanism.</p><p><strong>Methods: </strong>ICH model was constructed in C57BL/6 mice. Neurological deficit of ICH mice was evaluated. HE detected pathological changes of mouse brain tissue. Immunofluorescence staining tested co-localization between HO-1 or NF-κB p65 and IBA1. The expressions of gene and proteins were detected by RT-qPCR and Western blot, respectively. Flow cytometry determined microglial polarization phenotype and neuron apoptosis. Cell viability of neuron was assessed by CCK-8. Red blood cells labeled by PKH-26 and co-cultured with microglia for examining microglial erythrophagocytosis.</p><p><strong>Results: </strong>Both HO-1 and NF-κB p65 phosphorylation were elevated in brain tissues of ICH mice. ZnPP, a HO-1 inhibitor, could exacerbate microglial M1 polarization and nerve injury, as well as repress microglial erythrophagocytosis in vitro and hematoma clearance in vivo. On the contrary, Tat-NBD, a NF-κB inhibitor, greatly suppressed microglial M1 polarization, and induced M2 polarization and microglial erythrophagocytosis, thus improving nerve injury and hematoma clearance after ICH. Notably, it was observed that NF-κB p65 could be activated by ZnPP treatment, and the regulatory roles of ZnPP on microglial polarization and erythrophagocytosis after ICH in vivo and in vitro were all diminished by Tat-NBD.</p><p><strong>Conclusion: </strong>Therefore, our data demonstrated that HO-1 alleviated nerve injury and induced M2 polarization and phagocytosis of microglia after ICH via inhibiting NF-κB signaling pathway, which could provide deepen the pathological understanding of ICH and provide potential intervention targets and drug candidate for ICH.</p>","PeriodicalId":19142,"journal":{"name":"Neuroscience","volume":" ","pages":"17-27"},"PeriodicalIF":2.9000,"publicationDate":"2024-12-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Neuroscience","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1016/j.neuroscience.2024.12.020","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"NEUROSCIENCES","Score":null,"Total":0}
引用次数: 0

Abstract

Background: Microglia polarization plays a crucial role in inflammatory injury of brain following intracerebral hemorrhage (ICH). Heme oxygenase-1 (HO-1) has demonstrated protective properties against inflammation and promote hematoma clearance after ICH. The objective of this study was to explore impacts of HO-1 on microglia polarization and phagocytosis after ICH, along with the underlying mechanism.

Methods: ICH model was constructed in C57BL/6 mice. Neurological deficit of ICH mice was evaluated. HE detected pathological changes of mouse brain tissue. Immunofluorescence staining tested co-localization between HO-1 or NF-κB p65 and IBA1. The expressions of gene and proteins were detected by RT-qPCR and Western blot, respectively. Flow cytometry determined microglial polarization phenotype and neuron apoptosis. Cell viability of neuron was assessed by CCK-8. Red blood cells labeled by PKH-26 and co-cultured with microglia for examining microglial erythrophagocytosis.

Results: Both HO-1 and NF-κB p65 phosphorylation were elevated in brain tissues of ICH mice. ZnPP, a HO-1 inhibitor, could exacerbate microglial M1 polarization and nerve injury, as well as repress microglial erythrophagocytosis in vitro and hematoma clearance in vivo. On the contrary, Tat-NBD, a NF-κB inhibitor, greatly suppressed microglial M1 polarization, and induced M2 polarization and microglial erythrophagocytosis, thus improving nerve injury and hematoma clearance after ICH. Notably, it was observed that NF-κB p65 could be activated by ZnPP treatment, and the regulatory roles of ZnPP on microglial polarization and erythrophagocytosis after ICH in vivo and in vitro were all diminished by Tat-NBD.

Conclusion: Therefore, our data demonstrated that HO-1 alleviated nerve injury and induced M2 polarization and phagocytosis of microglia after ICH via inhibiting NF-κB signaling pathway, which could provide deepen the pathological understanding of ICH and provide potential intervention targets and drug candidate for ICH.

HO-1可抑制NF-kB信号通路,从而介导脑出血中小胶质细胞的极化和吞噬作用。
背景:小胶质细胞极化在脑出血(ICH)后脑炎症损伤中起重要作用。血红素加氧酶-1 (HO-1)具有抗炎症和促进脑出血后血肿清除的保护作用。本研究旨在探讨HO-1对脑出血后小胶质细胞极化和吞噬的影响及其可能的机制。方法:建立C57BL/6小鼠脑出血模型。评估脑出血小鼠的神经功能缺损。HE检测小鼠脑组织病理改变。免疫荧光染色检测HO-1或NF-kB p65与IBA1的共定位。RT-qPCR和Western blot分别检测基因和蛋白的表达。流式细胞术检测小胶质细胞极化表型和神经元凋亡。CCK-8检测神经元细胞活力。用PKH-26标记的红细胞与小胶质细胞共培养检测小胶质细胞的红细胞吞噬作用。结果:脑出血小鼠脑组织HO-1和NF-kB p65磷酸化均升高。HO-1抑制剂ZnPP可加重小胶质细胞M1极化和神经损伤,抑制小胶质细胞体外红细胞吞噬和体内血肿清除。相反,NF-kB抑制剂Tat-NBD可显著抑制小胶质细胞M1极化,诱导M2极化和小胶质细胞红细胞吞噬,从而改善脑出血后的神经损伤和血肿清除。值得注意的是,我们观察到ZnPP可以激活NF-kB p65,并且ZnPP对脑出血后小胶质细胞极化和红细胞吞噬的调节作用在体内和体外都被dat - nbd减弱。结论:我们的数据表明,HO-1通过抑制NF-κB信号通路,减轻脑出血后神经损伤,诱导M2极化和小胶质细胞吞噬,可加深对脑出血的病理认识,为脑出血提供潜在的干预靶点和候选药物。
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 求助全文
来源期刊
Neuroscience
Neuroscience 医学-神经科学
CiteScore
6.20
自引率
0.00%
发文量
394
审稿时长
52 days
期刊介绍: Neuroscience publishes papers describing the results of original research on any aspect of the scientific study of the nervous system. Any paper, however short, will be considered for publication provided that it reports significant, new and carefully confirmed findings with full experimental details.
×
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
确定
请完成安全验证×
copy
已复制链接
快去分享给好友吧!
我知道了
右上角分享
点击右上角分享
0
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 布克学术 All rights reserved.
京ICP备2023020795号-1
ghs 京公网安备 11010802042870号
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术官方微信