IL-6 信号通过上调内皮细胞中的 DMT1 加速铁超载,从而促进主动脉夹层。

IF 8.2 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY International Journal of Biological Sciences Pub Date : 2024-08-06 eCollection Date: 2024-01-01 DOI:10.7150/ijbs.99511
Qiang Xie, Jianji Wang, Runqiao Li, Hao Liu, Yongliang Zhong, Qinfeng Xu, Yipeng Ge, Chengnan Li, Lizhong Sun, Junming Zhu
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引用次数: 0

摘要

主动脉夹层(AD)由内膜撕裂和主动脉介质撕脱引起,严重威胁患者的生命和器官功能。铁与夹层的形成和器官损伤密切相关,但内皮细胞(EC)铁离子转运障碍的机制仍不清楚。我们通过单细胞RNA测序数据发现了夹层中铁超载的特征性EC。在对铁稳态和差异表达基因进行交叉分析后,我们发现缺氧诱导因子-1α(HIF-1α)和二价金属转运体1(DMT1)是导致铁离子转运障碍的关键基因。随后,通过进一步交叉和验证,IL-6R 被确定为经典铁调控途径 JAK-STAT 激活的重要原因。在体内和体外,IL-6受体高表达和IL-6水平升高都会促进JAK1-STAT3磷酸化,导致HIF-1α蛋白水平升高。升高的 HIF-1α 与 DMT1 基因的 5'-UTR 序列明确结合,并通过转录促进 DMT1 的表达,从而增加 Fe2+ 的积累和内质网应激(ERS)。用去铁胺和托珠单抗阻断IL-6R和游离铁能显著延长夹层小鼠的存活时间并减少主动脉和器官损伤。对AD患者和其他患者围手术期数据的比较显示,高游离铁、IL-6和ERS水平是AD患者的特征,并与预后相关。总之,活化的IL-6/JAK1/STAT3信号轴通过增加HIF-1α上调DMT1的表达,从而增加细胞内Fe2+的积累和组织损伤,这提示了AD的潜在治疗靶点。
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IL-6 signaling accelerates iron overload by upregulating DMT1 in endothelial cells to promote aortic dissection.

Aortic dissection (AD), caused by tearing of the intima and avulsion of the aortic media, is a severe threat to patient life and organ function. Iron is closely related to dissection formation and organ injury, but the mechanism of iron ion transport disorder in endothelial cells (ECs) remains unclear. We identified the characteristic EC of dissection with iron overload by single-cell RNA sequencing data. After intersecting iron homeostasis and differentially expressed genes, it was found that hypoxia-inducible factor-1α (HIF-1α) and divalent metal transporter 1 (DMT1) are key genes for iron ion disorder. Subsequently, IL-6R was identified as an essential reason for the JAK-STAT activation, a classical iron regulation pathway, through further intersection and validation. In in vivo and in vitro, both high IL-6 receptor expression and elevated IL-6 levels promote JAK1-STAT3 phosphorylation, leading to increased HIF-1α protein levels. Elevated HIF-1α binds explicitly to the 5'-UTR sequence of the DMT1 gene and transcriptionally promotes DMT1 expression, thereby increasing Fe2+ accumulation and endoplasmic reticulum stress (ERS). Blocking IL-6R and free iron with deferoxamine and tocilizumab significantly prolonged survival and reduced aortic and organ damage in dissection mice. A comparison of perioperative data between AD patients and others revealed that high free iron, IL-6, and ERS levels are characteristics of AD patients and are correlated with prognosis. In conclusion, activated IL-6/JAK1/STAT3 signaling axis up-regulates DMT1 expression by increasing HIF-1α, thereby increasing intracellular Fe2+ accumulation and tissue injury, which suggests a potential therapeutic target for AD.

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来源期刊
International Journal of Biological Sciences
International Journal of Biological Sciences 生物-生化与分子生物学
CiteScore
16.90
自引率
1.10%
发文量
413
审稿时长
1 months
期刊介绍: The International Journal of Biological Sciences is a peer-reviewed, open-access scientific journal published by Ivyspring International Publisher. It dedicates itself to publishing original articles, reviews, and short research communications across all domains of biological sciences.
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