Study on the mechanism of glucocorticoid receptor mitochondrial translocation and glucocorticoid-induced apoptosis in macrophages.

IF 2.9 4区医学 Q3 IMMUNOLOGY

Immunopharmacology and Immunotoxicology Pub Date : 2024-08-01 Epub Date: 2024-06-23 DOI:10.1080/08923973.2024.2366867

Xiaoqing Zhao, Xinglan Huang, Caifeng Huang, Xingrong Wang, Yuqi Yang, Ruonan Dang, Suiying Zhang, Yuqiong Deng, Peng Yan, Yiye Zhou, Ping Fan, Xiping Cheng

{"title":"Study on the mechanism of glucocorticoid receptor mitochondrial translocation and glucocorticoid-induced apoptosis in macrophages.","authors":"Xiaoqing Zhao, Xinglan Huang, Caifeng Huang, Xingrong Wang, Yuqi Yang, Ruonan Dang, Suiying Zhang, Yuqiong Deng, Peng Yan, Yiye Zhou, Ping Fan, Xiping Cheng","doi":"10.1080/08923973.2024.2366867","DOIUrl":null,"url":null,"abstract":"Objective: Our research aimed to investigate the therapeutic effects of Tubastatin-A, a glucocorticoid receptor (GR) mitochondrial translocation inhibitor, and mitoquinone (MitoQ), an antioxidant, on attenuating dexamethasone (DEX)-induced macrophage apoptosis.Methods: We treated RAW264.7 macrophages with different combinations of DEX and either Tubastatin-A or MitoQ. Parameters such as mitochondrial GR translocation, mitochondrial reactive oxygen species levels, mitochondrial membrane potential, mitochondrial permeability transition pore opening, cytochrome C efflux to the cytosol, and apoptosis were subsequently evaluated in the different treatment groups via qRT-PCR, western blotting, and immunofluorescence assays.Results: DEX intervention increased the translocation of GRs into the mitochondria, while reducing the expression of the mitochondrial gene MT-CO1 and the activity of mitochondrial respiratory chain complex IV in macrophages. In addition, DEX administration increased mtROS levels, mitochondrial permeability transition pore opening, and mitochondrial cytochrome C release in macrophages, which promoted their apoptosis. We found that Tubastatin-A inhibited mitochondrial GR translocation and reversed the DEX-induced increase in GR levels within the mitochondria. Furthermore, Tubastatin-A mitigated various mitochondrial changes induced by DEX, including reducing the efflux of mitochondrial cytochrome C and inhibiting macrophage apoptosis. Similarly, MitoQ exerted its effects on macrophage apoptosis by reducing mtROS levels through the mitochondrial pathway.Conclusions: The DEX-mediated translocation of GR into mitochondria disrupts the mitochondrial function of macrophages, which induces their apoptosis. By inhibiting mitochondrial translocation of GR and reducing mtROS levels, Tubastatin-A and MitoQ can effectively attenuate macrophage apoptosis, which has clinical implications for reducing the notable side effects associated with glucocorticoid use.","PeriodicalId":13420,"journal":{"name":"Immunopharmacology and Immunotoxicology","volume":null,"pages":null},"PeriodicalIF":2.9000,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Immunopharmacology and Immunotoxicology","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1080/08923973.2024.2366867","RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2024/6/23 0:00:00","PubModel":"Epub","JCR":"Q3","JCRName":"IMMUNOLOGY","Score":null,"Total":0}

引用次数: 0

Abstract

Objective: Our research aimed to investigate the therapeutic effects of Tubastatin-A, a glucocorticoid receptor (GR) mitochondrial translocation inhibitor, and mitoquinone (MitoQ), an antioxidant, on attenuating dexamethasone (DEX)-induced macrophage apoptosis.

Methods: We treated RAW264.7 macrophages with different combinations of DEX and either Tubastatin-A or MitoQ. Parameters such as mitochondrial GR translocation, mitochondrial reactive oxygen species levels, mitochondrial membrane potential, mitochondrial permeability transition pore opening, cytochrome C efflux to the cytosol, and apoptosis were subsequently evaluated in the different treatment groups via qRT-PCR, western blotting, and immunofluorescence assays.

Results: DEX intervention increased the translocation of GRs into the mitochondria, while reducing the expression of the mitochondrial gene MT-CO1 and the activity of mitochondrial respiratory chain complex IV in macrophages. In addition, DEX administration increased mtROS levels, mitochondrial permeability transition pore opening, and mitochondrial cytochrome C release in macrophages, which promoted their apoptosis. We found that Tubastatin-A inhibited mitochondrial GR translocation and reversed the DEX-induced increase in GR levels within the mitochondria. Furthermore, Tubastatin-A mitigated various mitochondrial changes induced by DEX, including reducing the efflux of mitochondrial cytochrome C and inhibiting macrophage apoptosis. Similarly, MitoQ exerted its effects on macrophage apoptosis by reducing mtROS levels through the mitochondrial pathway.

Conclusions: The DEX-mediated translocation of GR into mitochondria disrupts the mitochondrial function of macrophages, which induces their apoptosis. By inhibiting mitochondrial translocation of GR and reducing mtROS levels, Tubastatin-A and MitoQ can effectively attenuate macrophage apoptosis, which has clinical implications for reducing the notable side effects associated with glucocorticoid use.

查看原文本刊更多论文

糖皮质激素受体线粒体转位和糖皮质激素诱导巨噬细胞凋亡的机制研究

研究目的我们的研究旨在探讨糖皮质激素受体（GR）线粒体转位抑制剂Tubastatin-A和抗氧化剂线粒体醌（MitoQ）对减轻地塞米松（DEX）诱导的巨噬细胞凋亡的治疗效果：我们用DEX和Tubastatin-A或MitoQ的不同组合处理RAW264.7巨噬细胞。随后，通过qRT-PCR、Western印迹和免疫荧光检测评估了不同处理组的线粒体GR转位、线粒体活性氧水平、线粒体膜电位、线粒体通透性转换孔开放、细胞色素C流出细胞膜和细胞凋亡等参数：结果：DEX干预增加了GRs向线粒体的转运，同时降低了巨噬细胞中线粒体基因MT-CO1的表达和线粒体呼吸链复合物IV的活性。此外，DEX还能增加巨噬细胞中的mtROS水平、线粒体通透性转换孔开放和线粒体细胞色素C释放，从而促进巨噬细胞凋亡。我们发现，Tubastatin-A 可抑制线粒体 GR 转位，并逆转 DEX 诱导的线粒体内 GR 水平升高。此外，Tubastatin-A还能缓解DEX诱导的各种线粒体变化，包括减少线粒体细胞色素C外流和抑制巨噬细胞凋亡。同样，MitoQ通过线粒体途径降低mtROS水平，从而对巨噬细胞凋亡产生影响：结论：DEX 介导的 GR 转位至线粒体会破坏巨噬细胞的线粒体功能，从而诱导巨噬细胞凋亡。通过抑制GR的线粒体转运和降低mtROS水平，Tubastatin-A和MitoQ可有效减轻巨噬细胞凋亡，这对减少使用糖皮质激素带来的显著副作用具有临床意义。

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

Immunopharmacology and Immunotoxicology 医学-毒理学

CiteScore

5.40

自引率

0.00%

发文量

133

审稿时长

4-8 weeks

期刊介绍： The journal Immunopharmacology and Immunotoxicology is devoted to pre-clinical and clinical drug discovery and development targeting the immune system. Research related to the immunoregulatory effects of various compounds, including small-molecule drugs and biologics, on immunocompetent cells and immune responses, as well as the immunotoxicity exerted by xenobiotics and drugs. Only research that describe the mechanisms of specific compounds (not extracts) is of interest to the journal. The journal will prioritise preclinical and clinical studies on immunotherapy of disorders such as chronic inflammation, allergy, autoimmunity, cancer etc. The effects of small-drugs, vaccines and biologics against central immunological targets as well as cell-based therapy, including dendritic cell therapy, T cell adoptive transfer and stem cell therapy, are topics of particular interest. Publications pointing towards potential new drug targets within the immune system or novel technology for immunopharmacological drug development are also welcome. With an immunoscience focus on drug development, immunotherapy and toxicology, the journal will cover areas such as infection, allergy, inflammation, tumor immunology, degenerative disorders, immunodeficiencies, neurology, atherosclerosis and more. Immunopharmacology and Immunotoxicology will accept original manuscripts, brief communications, commentaries, mini-reviews, reviews, clinical trials and clinical cases, on the condition that the results reported are based on original, clinical, or basic research that has not been published elsewhere in any journal in any language (except in abstract form relating to paper communicated to scientific meetings and symposiums).