Wang Lueli, Shi Rui, Li Zhaoliang, Ma Ruoqiu, Wang Chongyu, Xu Changli, Guo Rong, Xiao Chuang, Du Xiaohua, Yang Weimin
Yunnan Key Laboratory of Pharmacology for Natural Products, Kunming Medical University, Kunming, People's Republic of China.
Pharmacy Department, The First People's Hospital of Zhaotong, Zhaotong, People's Republic of China.
J Inflamm Res. 2025 Jun 30;18:8563-8578. doi: 10.2147/JIR.S513004. eCollection 2025.
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.
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.
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.
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.
慢性阻塞性肺疾病（COPD）是一种病因复杂的疾病。白细胞介素-1β（IL-1β）等炎症因子的分泌以及氧化应激在COPD的发病机制中起重要作用。本文旨在研究COPD中氧化还原蛋白硫氧还蛋白（TRX）的变化以及TRX在IL-1β释放中所起的作用。
我们分析了基因表达综合数据库（GEO数据库）中COPD肺组织的单细胞RNA测序（scRNA-seq）数据。通过肺泡巨噬细胞（AM）的蛋白质活性分析评估TRX表达水平和活性的变化。使用Monocle2和分子动力学（MD）分析TRX通过哪些途径实现对炎症反应的调节。随后通过构建体内和体外模型对分析结果进行验证。
通过scRNA-seq鉴定出特异性合成IL-1β的AM。COPD患者的IL-1β+ AM中TRX表达水平无变化，但蛋白质抗氧化活性降低。我们证实在COPD小鼠模型和THP-1细胞模型中氧化型TRX（oxTRX）增加，还原型TRX（reTRX）减少。reTRX的减少伴随着NLRP3活性的上调，NLRP3在该亚组中对IL-1β的合成起催化作用。这随后在香烟烟雾诱导的THP-1细胞模型中得到证实。reTRX水平降低伴随着NLRP3活性上调，NLRP3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reTRX减少后硫氧还蛋白相互作用蛋白（TXNIP）解聚。然后TNXIP与NLRP3相互作用并上调NLRP3活性，进而促进IL-1β释放。
我们的研究表明，COPD中reTRX发生异常改变，导致AM中NLRP3活性上调，从而增强IL-1β的产生。
