DNA demethylation mediated endogenous retroviruses transcription promotes aberrant T cell differentiation in systemic lupus erythematosus via RIG-I pathway.

IF 10.8 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL
Xiaoli Min, Yaqin Yu, Zhi Hu, Lianlian Ouyang, Yueqi Qiu, Hongjun Zhao, Jiali Wu, Chun Zou, Meiling Zheng, Shuang Yang, Sujie Jia, Di Yu, Qianjin Lu, Ming Zhao
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Abstract

Background: Systemic lupus erythematosus (SLE) displays quantitative and/or qualitative deficiencies of regulatory T cells (Treg) and expansion and hyperfunction of pathogenic T cells. However, the underlying mechanism of dysregulated T lymphocyte differentiation in SLE remains unclear.

Methods: Transcriptome sequencing and functional assays were performed to elucidate the mechanisms and function of human endogenous retroviruses (HERVs) on T cell differentiation in SLE. The effect of retinoic acid-inducible gene I (RIG-I) deficiency on lupus pathogenesis were assessed in lupus-like mouse models.

Findings: We found that many transcripts derived from HERVs were highly expressed in CD4+ T cells from patients with SLE due to DNA hypomethylation, some of which were characterized by double strand RNAs (dsRNAs). Excessive dsRNAs promoted Th1 cell differentiation and inhibited Treg cell differentiation via the activation of the dsRNA sensor RIG-I pathway, accompanied by a high level of type I interferons (IFN-I) and interferon-stimulated gene expression. In contrast, T cell-specific ablation of RIG-I alleviated disease progression in lupus-like mouse models by reducing the proportion of pathogenic T cells, restoring the percentage of Treg cells, and diminishing cytokine and autoantibody release. Importantly, we demonstrated that the dsRNA-induced RIG-I/IRF3 pathway regulated Th1 cell differentiation in a IFN-I/STAT1 signalling-dependent manner and inhibited Treg cell differentiation via SMAD3 signalling.

Interpretation: Our findings reveal the roles of HERV-derived dsRNA/RIG-I pathway in regulating the aberrant differentiation of T cells in patients with SLE and may facilitate the development of potential therapeutic targets for SLE.

Funding: A full list of funding sources can be found in the Funding section.

DNA去甲基化介导的内源性逆转录病毒转录通过rig - 1途径促进系统性红斑狼疮中T细胞的异常分化。
背景:系统性红斑狼疮(SLE)表现出调节性T细胞(Treg)的定量和/或定性缺陷以及致病性T细胞的扩增和功能亢进。然而,SLE中T淋巴细胞分化失调的潜在机制尚不清楚。方法:通过转录组测序和功能分析,阐明人内源性逆转录病毒(herv)对SLE患者T细胞分化的作用机制和功能。在狼疮样小鼠模型中评估视黄酸诱导基因I (RIG-I)缺乏对狼疮发病机制的影响。研究结果:我们发现,由于DNA低甲基化,许多来自herv的转录本在SLE患者的CD4+ T细胞中高表达,其中一些以双链rna (dsRNAs)为特征。过量的dsRNA通过激活dsRNA传感器RIG-I通路促进Th1细胞分化,抑制Treg细胞分化,同时伴有高水平的I型干扰素(IFN-I)和干扰素刺激基因表达。相比之下,T细胞特异性消融rig - 1通过降低致病性T细胞的比例,恢复Treg细胞的百分比,减少细胞因子和自身抗体的释放,缓解狼疮样小鼠模型的疾病进展。重要的是,我们证明了dsrna诱导的RIG-I/IRF3通路以IFN-I/STAT1信号依赖的方式调节Th1细胞分化,并通过SMAD3信号传导抑制Treg细胞分化。解释:我们的研究结果揭示了herv衍生的dsRNA/RIG-I通路在调节SLE患者T细胞异常分化中的作用,并可能促进SLE潜在治疗靶点的开发。资金:资金来源的完整列表可以在资金部分找到。
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来源期刊
EBioMedicine
EBioMedicine Biochemistry, Genetics and Molecular Biology-General Biochemistry,Genetics and Molecular Biology
CiteScore
17.70
自引率
0.90%
发文量
579
审稿时长
5 weeks
期刊介绍: eBioMedicine is a comprehensive biomedical research journal that covers a wide range of studies that are relevant to human health. Our focus is on original research that explores the fundamental factors influencing human health and disease, including the discovery of new therapeutic targets and treatments, the identification of biomarkers and diagnostic tools, and the investigation and modification of disease pathways and mechanisms. We welcome studies from any biomedical discipline that contribute to our understanding of disease and aim to improve human health.
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