减少硫氧还蛋白通过NLRP3调节IL-1β+肺泡巨噬细胞在COPD中的分泌。

IF 4.2 2区 医学 Q2 IMMUNOLOGY
Journal of Inflammation Research Pub Date : 2025-06-30 eCollection Date: 2025-01-01 DOI:10.2147/JIR.S513004
Lueli Wang, Rui Shi, Zhaoliang Li, Ruoqiu Ma, Chongyu Wang, Changli Xu, Rong Guo, Chuang Xiao, Xiaohua Du, Weimin Yang
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引用次数: 0

摘要

目的:慢性阻塞性肺疾病(COPD)是一种病因复杂的疾病。IL-1β、氧化应激等炎症因子的分泌在COPD发病中起重要作用。本文旨在探讨氧化还原蛋白硫氧还蛋白(TRX)在COPD中的变化及其在IL-1β释放中的作用。方法:我们分析GEO数据库中COPD肺组织单细胞RNA测序(scRNA-seq)数据。通过肺泡巨噬细胞(AM)蛋白活性分析评估TRX表达水平和活性的变化。利用Monocle2和分子动力学(MD)分析TRX通过哪些途径实现了炎症反应的调控。随后通过构建体内和体外模型验证了分析结果。结果:通过scRNA-seq鉴定出特异性合成IL-1β的AM。慢性阻塞性肺病患者IL-1β+ AM中TRX表达水平无变化,蛋白抗氧化活性降低。我们证实在COPD小鼠模型和THP-1细胞模型中氧化TRX (oxTRX)增加,还原TRX (reTRX)减少。在该亚组中,reTRX的降低伴随着NLRP3活性的上调,其在IL-1β的合成中起催化作用。随后在香烟烟雾诱导的THP-1细胞模型中证实了这一点。reTRX水平的降低伴随着NLRP3活性的上调,其在IL-1β的合成中起促进作用。我们通过MD和免疫共沉淀(CO-IP)确定了reTRX还原之后是硫氧还蛋白相互作用蛋白(TXNIP)的解聚。然后,TNXIP与NLRP3相互作用,上调NLRP3活性,进而促进IL-1β的释放。结论:我们的研究表明,在COPD中,reTRX异常改变,导致AM中NLRP3活性上调,从而增加IL-1β的产生。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Reduced Thioredoxin Regulates IL-1β Secretion via NLRP3 of IL-1β+ Alveolar Macrophages in COPD.

Objective: Chronic obstructive pulmonary disease (COPD) is a disease with a complex etiology. The secretion of inflammatory factors, such as IL-1β and oxidative stress, plays an important role in the pathogenesis of COPD. The aim of this paper is to investigate the changes in the redox protein thioredoxin (TRX) in COPD and the role TRX plays in IL-1β release.

Methods: We analyzed data from single-cell RNA sequencing (scRNA-seq) of COPD lung tissue in the GEO database. Changes in TRX expression levels and activity were assessed by protein activity analysis of alveolar macrophages(AM). Using Monocle2 and molecular dynamics(MD) to analyze which pathways through TRX achieves regulation of the inflammatory response. The analytical results were subsequently validated by constructing vivo and vitro models.

Results: AM that specifically synthesize IL-1β were identified by scRNA-seq. No change in TRX expression levels and decreased protein antioxidant activity in IL-1β+ AM with COPD. We confirmed an increase in oxidized TRX (oxTRX) and a decrease in reduced TRX (reTRX) in COPD mouse model and THP-1 cell model. The decrease in reTRX was accompanied by the upregulation of NLRP3 activity, which played a catalytic role in the synthesis of IL-1β in this subgroup. This was subsequently confirmed in a cigarette smoke-induced THP-1 cell model. A decrease in reTRX level accompanied by an upregulation of NLRP3 activity, which plays a facilitating role in the synthesis of IL-1β. We determined that reTRX reduction was followed by depolymerization of thioredoxin-interacting protein (TXNIP) through MD and immune co-precipitation (CO-IP). Then TNXIP interacted with NLRP3 and up-regulate NLRP3 activity, which in turn promoted IL-1β release.

Conclusion: Our study shows that the reTRX is abnormally altered in COPD and leads to the upregulation of NLRP3 activity in AM to enhance IL-1β production.

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来源期刊
Journal of Inflammation Research
Journal of Inflammation Research Immunology and Microbiology-Immunology
CiteScore
6.10
自引率
2.20%
发文量
658
审稿时长
16 weeks
期刊介绍: An international, peer-reviewed, open access, online journal that welcomes laboratory and clinical findings on the molecular basis, cell biology and pharmacology of inflammation.
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