iTreg细胞分泌的IL10通过使lncRNA HAR1A转录失活来抑制SMARCD1介导的iNOS激活,从而缓解狼疮肾炎。

IF 3.3 4区 医学 Q3 IMMUNOLOGY
Autoimmunity Pub Date : 2024-12-01 Epub Date: 2024-11-05 DOI:10.1080/08916934.2024.2423758
Ya Liu, Pei Li, Longkun Wang, Luojia Jiang, Zhengfu Li, Yu Mei, Weijuan Deng
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引用次数: 0

摘要

狼疮性肾炎(LN)是系统性红斑狼疮(SLE)的一种高发并发症。长非编码 RNA(lncRNA)是包括 LN 在内的多种人类疾病的重要调节因子。在本研究中,我们从在线 GEO 数据库中筛选出在 LN 患者血液样本中差异表达的 lncRNA。通过进一步的 RT-qPCR 分析,我们发现在 LN 患者的血液样本中,lncRNA 高加速区 1 A(HAR1A)的上调最为显著。在功能上,我们发现 HAR1A 的过度表达会加重 LPS 诱导的损伤和炎症。根据生物信息学分析和机制实验的结果,我们确定 HAR1A 与 miR-149-3p 结合,通过竞争性内源性 RNA(ceRNA)机制上调 SMARCD1。事实证明,iNOS 是一种炎症诱导因子。在这里,我们发现 HAR1A/miR-149-3p/SMARCD1 通过提高 iNOS 启动子中的 H3K27ac 水平来上调 iNOS 的表达。此前,我们证明了 CD8+CD103+ iTreg 细胞能减轻肾小球内皮细胞损伤。此外,我们还证明了 CD8+ CD103+ iTreg 细胞分泌的 IL-10 可通过抑制 NF-κB 通路的激活来下调 HAR1A 的表达。总之,本研究提供的证据揭示了 CD8+CD103+ iTreg 细胞在 LN 中阻断的新型分子通路。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
iTreg cells-secreted IL10 alleviates lupus nephritis through inactivating lncRNA HAR1A transcription to suppress SMARCD1-mediated iNOS activation.

Lupus nephritis (LN) is a highly prevalent complication of systemic lupus erythematosus (SLE). Long non-coding RNAs (lncRNAs) are essential modulators in multiple types of human diseases, including LN. In the current study, we searched on online GEO database to select out lncRNAs that were differentially expressed in blood samples of LN patients. Through further RT-qPCR analysis, we found that lncRNA Highly Accelerated Region 1 A (HAR1A) is most significantly upregulated in blood samples of LN patients. Functionally, we detected that overexpression of HAR1A could aggravate LPS-induced injury and inflammation. According to the results of bioinformatics analysis and mechanism experiments, we determined that HAR1A binds with miR-149-3p to upregulate SMARCD1 through competing endogenous RNA (ceRNA) mechanism. It has been proven that iNOS is an inflammation inducer. Here, we found that HAR1A/miR-149-3p/SMARCD1 upregulates iNOS expression through enhancing H3K27ac level in iNOS promoter. Previously, we proved that CD8+CD103+ iTreg cells could alleviate glomerular endothelial cell injury. Moreover, we demonstrated that CD8 + CD103+ iTreg cells-secreted IL-10 downregulated HAR1A expression by impeding NF-κB pathway activation. In conclusion, this study provides evidences revealing a novel molecular pathway blocked by CD8+CD103+ iTreg cells in LN.

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来源期刊
Autoimmunity
Autoimmunity 医学-免疫学
CiteScore
5.70
自引率
8.60%
发文量
59
审稿时长
6-12 weeks
期刊介绍: Autoimmunity is an international, peer reviewed journal that publishes articles on cell and molecular immunology, immunogenetics, molecular biology and autoimmunity. Current understanding of immunity and autoimmunity is being furthered by the progress in new molecular sciences that has recently been little short of spectacular. In addition to the basic elements and mechanisms of the immune system, Autoimmunity is interested in the cellular and molecular processes associated with systemic lupus erythematosus, rheumatoid arthritis, Sjogren syndrome, type I diabetes, multiple sclerosis and other systemic and organ-specific autoimmune disorders. The journal reflects the immunology areas where scientific progress is most rapid. It is a valuable tool to basic and translational researchers in cell biology, genetics and molecular biology of immunity and autoimmunity.
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