DNA demethylation mediated endogenous retroviruses transcription promotes aberrant T cell differentiation in systemic lupus erythematosus via RIG-I pathway.
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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引用次数: 0
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.
EBioMedicineBiochemistry, 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.