巨噬细胞源性外泌体miRNA-141通过靶向NLRP3引发内皮细胞脓毒症,加速脓毒症进展

Feng Zhan, Jun Zhang, Ping He, Wenteng Chen, Yanhong Ouyang
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引用次数: 0

摘要

败血症是一种因感染失控而导致器官功能严重失调的危重病,严重影响内皮细胞。巨噬细胞通过旁分泌作用在败血症中发挥着重要作用,但其在败血症发病机制中的作用机制仍不明确。研究目的我们旨在探索低 miR-141 表达的巨噬细胞衍生外泌体如何促进内皮细胞(ECs)的脓毒症。我们从 THP-1 细胞上清液中分离并鉴定了外泌体。使用流式细胞仪、CCK-8和透孔试验评估了miR-141模拟物/抑制剂对人脐静脉内皮细胞(HUVECs)凋亡、增殖和侵袭的影响。通过 Western 印迹分析了关键的热蛋白相关蛋白,包括 caspase-1、IL-18、IL-1β、NLR 家族含吡啶域 3(NLRP3)、ASC 和裂解-GSDMD。利用 RNAhybrid v2.2 和双荧光素酶报告实验研究了 miR-141 和 NLRP3 之间的相互作用。通过 qPCR 和 Western 印迹分别检测了外泌体 miR-141 抑制剂处理后 NLRP3 的 mRNA 和蛋白水平。miR-141模拟物减少了HUVECs的细胞死亡和热蛋白相关蛋白的表达,而抑制剂则产生了相反的效果,增加了细胞死亡和热蛋白表达。此外,巨噬细胞衍生的外泌体 miR-141 抑制剂增加了 HUVECs 中的细胞死亡和热蛋白相关蛋白的表达。巨噬细胞通过分泌减少的外泌体miR-141来激活NLRP3介导的ECs脓毒症,从而促进脓毒症的进展,这可能是脓毒症治疗的一个有价值的靶点。
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Macrophage-derived exosomal miRNA-141 triggers endothelial cell pyroptosis by targeting NLRP3 to accelerate sepsis progression
Sepsis, critical condition marked by severe organ dysfunction from uncontrolled infection, involves the endothelium significantly. Macrophages, through paracrine actions, play a vital role in sepsis, but their mechanisms in sepsis pathogenesis remain elusive. Objective: We aimed to explore how macrophage-derived exosomes with low miR-141 expression promote pyroptosis in endothelial cells (ECs). Exosomes from THP-1 cell supernatant were isolated and characterized. The effects of miR-141 mimic/inhibitor on apoptosis, proliferation, and invasion of Human Umbilical Vein Endothelial Cells (HUVECs) were assessed using flow cytometry, CCK-8, and transwell assays. Key pyroptosis-related proteins, including caspase-1, IL-18, IL-1β, NLR Family Pyrin Domain Containing 3 (NLRP3), ASC, and cleaved-GSDMD, were analyzed via Western blot. The interaction between miR-141 and NLRP3 was studied using RNAhybrid v2.2 and dual-Luciferase reporter assays. The mRNA and protein level of NLRP3 after exosomal miR-141 inhibitor treatment was detected by qPCR and Western blot, respectively. Exosomes were successfully isolated. miR-141 mimic reduced cell death and pyroptosis-related protein expression in HUVECs, while the inhibitor had opposite effects, increasing cell death, and enhancing pyroptosis protein expression. Additionally, macrophage-derived exosomal miR-141 inhibitor increased cell death and pyroptosis-related proteins in HUVECs. miR-141 inhibits NLRP3 transcription. Macrophages facilitate sepsis progression by secreting miR-141 decreased exosomes to activate NLRP3-mediated pyroptosis in ECs, which could be a potentially valuable target of sepsis therapy.
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来源期刊
CiteScore
4.00
自引率
0.00%
发文量
88
审稿时长
15 weeks
期刊介绍: International Journal of Immunopathology and Pharmacology is an Open Access peer-reviewed journal publishing original papers describing research in the fields of immunology, pathology and pharmacology. The intention is that the journal should reflect both the experimental and clinical aspects of immunology as well as advances in the understanding of the pathology and pharmacology of the immune system.
期刊最新文献
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