GSNOR negatively regulates the NLRP3 inflammasome via S-nitrosation of MAPK14

IF 21.8 1区 医学 Q1 IMMUNOLOGY
Qianjin Liu, Lijin Jiao, Mao-Sen Ye, Zhiyu Ma, Jinsong Yu, Ling-Yan Su, Wei-Yin Zou, Lu-Xiu Yang, Chang Chen, Yong-Gang Yao
{"title":"GSNOR negatively regulates the NLRP3 inflammasome via S-nitrosation of MAPK14","authors":"Qianjin Liu, Lijin Jiao, Mao-Sen Ye, Zhiyu Ma, Jinsong Yu, Ling-Yan Su, Wei-Yin Zou, Lu-Xiu Yang, Chang Chen, Yong-Gang Yao","doi":"10.1038/s41423-024-01155-9","DOIUrl":null,"url":null,"abstract":"Hyperactivation of the NLRP3 inflammasome has been implicated in the pathogenesis of numerous diseases. However, the precise molecular mechanisms that modulate the transcriptional regulation of NLRP3 remain largely unknown. In this study, we demonstrated that S-nitrosoglutathione reductase (GSNOR) deficiency in macrophages leads to significant increases in the Nlrp3 and Il-1β expression levels and interleukin-1β (IL-1β) secretion in response to NLRP3 inflammasome stimulation. Furthermore, in vivo experiments utilizing Gsnor−/− mice revealed increased disease severity in both lipopolysaccharide (LPS)-induced septic shock and dextran sodium sulfate (DSS)-induced colitis models. Additionally, we showed that both LPS-induced septic shock and DSS-induced colitis were ameliorated in Gsnor−/− Nlrp3−/− double-knockout (DKO) mice. Mechanistically, GSNOR deficiency increases the S-nitrosation of mitogen-activated protein kinase 14 (MAPK14) at the Cys211 residue and augments MAPK14 kinase activity, thereby promoting Nlrp3 and Il-1β transcription and stimulating NLRP3 inflammasome activity. Our findings suggested that GSNOR is a regulator of the NLRP3 inflammasome and that reducing the level of S-nitrosylated MAPK14 may constitute an effective strategy for alleviating diseases associated with NLRP3-mediated inflammation.","PeriodicalId":9950,"journal":{"name":"Cellular &Molecular Immunology","volume":null,"pages":null},"PeriodicalIF":21.8000,"publicationDate":"2024-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Cellular &Molecular Immunology","FirstCategoryId":"3","ListUrlMain":"https://www.nature.com/articles/s41423-024-01155-9","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"IMMUNOLOGY","Score":null,"Total":0}
引用次数: 0

Abstract

Hyperactivation of the NLRP3 inflammasome has been implicated in the pathogenesis of numerous diseases. However, the precise molecular mechanisms that modulate the transcriptional regulation of NLRP3 remain largely unknown. In this study, we demonstrated that S-nitrosoglutathione reductase (GSNOR) deficiency in macrophages leads to significant increases in the Nlrp3 and Il-1β expression levels and interleukin-1β (IL-1β) secretion in response to NLRP3 inflammasome stimulation. Furthermore, in vivo experiments utilizing Gsnor−/− mice revealed increased disease severity in both lipopolysaccharide (LPS)-induced septic shock and dextran sodium sulfate (DSS)-induced colitis models. Additionally, we showed that both LPS-induced septic shock and DSS-induced colitis were ameliorated in Gsnor−/− Nlrp3−/− double-knockout (DKO) mice. Mechanistically, GSNOR deficiency increases the S-nitrosation of mitogen-activated protein kinase 14 (MAPK14) at the Cys211 residue and augments MAPK14 kinase activity, thereby promoting Nlrp3 and Il-1β transcription and stimulating NLRP3 inflammasome activity. Our findings suggested that GSNOR is a regulator of the NLRP3 inflammasome and that reducing the level of S-nitrosylated MAPK14 may constitute an effective strategy for alleviating diseases associated with NLRP3-mediated inflammation.

Abstract Image

GSNOR 通过 S-亚硝基化 MAPK14 负向调节 NLRP3 炎症体
NLRP3 炎性体的过度激活与多种疾病的发病机制有关。然而,调节 NLRP3 转录调控的确切分子机制在很大程度上仍然未知。在这项研究中,我们证实了巨噬细胞中 S-亚硝基谷胱甘肽还原酶(GSNOR)的缺乏会导致 Nlrp3 和 Il-1β 的表达水平以及白细胞介素-1β(IL-1β)的分泌在 NLRP3 炎性体刺激下显著增加。此外,利用 Gsnor-/- 小鼠进行的体内实验显示,在脂多糖(LPS)诱导的脓毒性休克和右旋糖酐硫酸钠(DSS)诱导的结肠炎模型中,疾病的严重程度都有所增加。此外,我们还发现,Gsnor-/- Nlrp3-/- 双基因敲除(DKO)小鼠的脓毒性休克和右旋糖酐硫酸钠(DSS)诱导的结肠炎均有所改善。从机理上讲,GSNOR的缺乏增加了丝裂原活化蛋白激酶14(MAPK14)在Cys211残基上的S-亚硝基化,增强了MAPK14激酶的活性,从而促进了Nlrp3和Il-1β的转录,刺激了NLRP3炎性体的活性。我们的研究结果表明,GSNOR 是 NLRP3 炎症体的调控因子,降低 S-亚硝基化 MAPK14 的水平可能是缓解 NLRP3 介导的炎症相关疾病的有效策略。
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 求助全文
来源期刊
CiteScore
31.20
自引率
1.20%
发文量
903
审稿时长
1 months
期刊介绍: Cellular & Molecular Immunology, a monthly journal from the Chinese Society of Immunology and the University of Science and Technology of China, serves as a comprehensive platform covering both basic immunology research and clinical applications. The journal publishes a variety of article types, including Articles, Review Articles, Mini Reviews, and Short Communications, focusing on diverse aspects of cellular and molecular immunology.
×
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