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IF 4.2 2区医学 Q2 IMMUNOLOGY

Journal of Inflammation Research Pub Date : 2025-03-17 eCollection Date: 2025-01-01 DOI:10.2147/JIR.S507076

Xueliang Pei, Facai Cui, Yu Chen, Zhiyuan Yang, Zhouliang Xie, Yongjin Wen

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引用次数: 0

摘要

目的：动脉粥样硬化（AS）是一种由脂质代谢失调引起的慢性炎症性疾病。目前已证实，氧化低密度脂蛋白（ox-LDL）诱导的巨噬细胞炎症和铁变态反应在动脉粥样硬化中起着重要作用。然而，氧化低密度脂蛋白诱导巨噬细胞炎症的机制还需要进一步研究：为研究其作用机制，我们构建了由 ox-LDL 诱导的巨噬细胞衍生的泡沫细胞模型。使用酶联免疫吸附试验（ELISA）评估了白细胞介素（IL）-6、IL-1β和肿瘤坏死因子（TNF）-α的水平。油红 O 染色法用于检测细胞内脂质积累水平。评估了乳酸脱氢酶（LDH）、丙二醛（MDA）、活性氧（ROS）和 Fe2+ 的水平。双荧光素酶和 RNA 结合蛋白免疫沉淀（RIP）实验验证了 microRNA（miR）-214-3p 与谷胱甘肽过氧化物酶 4（GPX4）之间的结合关系：结果：在氧化-LDL 诱导的巨噬细胞中，IL-6、IL-1β 和 TNF-α 的水平显著升高，同时脂质积累增加，表明促进了泡沫细胞的形成。此外，ox-LDL 还增加了 LDH、MDA、ROS 和 Fe2+。miR-214-3p 的表达与巨噬细胞中 ox-LDL 的浓度呈正相关。使用 miR-214-3p 抑制剂可减少巨噬细胞中的脂质积累、炎症反应和铁跃迁。双荧光素酶和 RIP 实验证实，miR-214-3p 能调节 GPX4 的转录。沉默的 GPX4 逆转了 miR-214-3p 抑制剂对氧化-LDL 诱导的巨噬细胞的炎症效应。结论：miR-214-3p 促进巨噬细胞的铁蛋白沉积和氧化-LDL 诱导的炎症。这一机制可能与 miR-214-3p 诱导的 GPX4 表达有关，这凸显了针对巨噬细胞炎症和铁蛋白沉积对强直性脊柱炎的治疗意义。

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miR-214-3p Promotes ox-LDL-Induced Macrophages Ferroptosis and Inflammation via GPX4.

Purpose: Atherosclerosis (AS) is a chronic inflammatory disease caused by the dysregulation of lipid metabolism. It has been established that oxidized low-density lipoprotein (ox-LDL)-induced macrophage inflammation and ferroptosis play important roles in AS. However, the mechanism by which ox-LDL induces inflammation in macrophages requires further investigation.

Materials and methods: A foam cell model derived from ox-LDL-induced macrophages was constructed to study its mechanism of action. The levels of interleukin (IL)-6, IL-1β, and tumor necrosis factor (TNF)-α were evaluated using an Enzyme-Linked Immunosorbent Assay (ELISA). Oil Red O staining was used to detect intracellular lipid accumulation levels. Lactate dehydrogenase (LDH), malondialdehyde (MDA), reactive oxygen species (ROS), and Fe²⁺ levels were assessed. Dual-luciferase and RNA-binding protein immunoprecipitation (RIP) experiments validated the binding relationship between microRNA (miR)-214-3p and glutathione peroxidase 4 (GPX4).

Results: The levels of IL-6, IL-1β, and TNF-α were significantly increased in ox-LDL-induced macrophages, accompanied by increased lipid accumulation, indicating the promotion of foam cell formation. Additionally, ox-LDL increased LDH, MDA, ROS, and Fe²⁺. The expression of miR-214-3p positively correlated with ox-LDL concentration in macrophages. Treatment with an miR-214-3p inhibitor reduces lipid accumulation, inflammatory responses, and ferroptosis in macrophages. Dual-luciferase and RIP experiments confirmed that miR-214-3p regulates GPX4 transcription. Silenced GPX4 reversed the inflammatory effects of the miR-214-3p inhibitor on ox-LDL-induced macrophages. Low GPX4 expression also increased lipid accumulation and ferroptosis in macrophages.

Conclusion: miR-214-3p promotes macrophage ferroptosis and inflammation induced by ox-LDL. This mechanism may be associated with miR-214-3p-induced GPX4 expression, which underscores the therapeutic significance of targeting macrophage inflammation and ferroptosis in addressing AS.

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来源期刊

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.