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Nanoparticle-Delivered siRNA Targeting NSUN4 Relieves Systemic Lupus Erythematosus through Declining
Bincheng Ren1, Kaini He2, Ning Wei3
1Department of Rheumatology and Immunology The Second Affiliated Hospital of Xi'an Jiaotong University Xi'an China.
Abstract:
5-Methylcytosine modification (m5C) is an important posttranscriptional regulatory mechanism of gene expression. Exhausted CD8+T cells contribute to the development of many major diseases; however, their exact role and relationship to m5C in systemic lupus erythematosus (SLE) remain unknown. In this study, we identified a CD7highCD74high CD8+T subgroup that were robustly expanded in SLE patients through single-cell transcriptome sequencing (scRNA-seq). CD7highCD74high CD8+T cells displayed exhausted features and exhibited a superior diagnostic value in SLE. Then, we explored the m5C landscape of SLE patients by performing m5C epitranscriptome sequencing (m5C-seq). ScRNA-seq and m5C-seq were conjointly analyzed to screen m5C-related therapeutic targets for SLE, and NOP2/Sun RNA methyltransferase 4 (NSUN4) was identified as a key regulator of SLE pathogenesis. Knockdown of NSUN4 downregulated CD74 expression via reduction of m5C and suppressed CD8+T cell exhaustion by declining CD44/mTOR (mechanistic target of rapamycin kinase)-mediated mitophagy. Finally, we verified that nanoparticle-delivered siRNA against Nusn4 decreased autoimmune reaction kidney damage in both spontaneous and pristane-induced SLE mouse models. In conclusion, we identify an exhausted CD7highCD74high CD8+T cell subset and propose the crucial role of NSUN4/CD74-induced dysregulation of mitophagy in SLE pathogenesis, and targeting NSUN4 is a promising treatment strategy for SLE patients.
Insights
Researchers identified an exhausted CD7highCD74high CD8+T cell subgroup in systemic lupus erythematosus (SLE). Targeting NSUN4, a key regulator, shows promise for treating SLE by reducing T cell exhaustion and kidney damage.
Area of Science:
- Immunology
- Epigenetics
- Molecular Biology
Background:
- 5-Methylcytosine (m5C) modification regulates gene expression post-transcriptionally.
- Exhausted CD8+T cells are implicated in various diseases, but their role in systemic lupus erythematosus (SLE) is unclear.
- Understanding m5C's role in SLE pathogenesis is crucial for developing new therapies.
Purpose of the Study:
- To identify specific CD8+T cell subsets involved in SLE pathogenesis.
- To investigate the m5C epitranscriptome in SLE patients.
- To identify and validate m5C-related therapeutic targets for SLE.
Main Methods:
- Single-cell transcriptome sequencing (scRNA-seq) to identify CD8+T cell subgroups.
- m5C epitranscriptome sequencing (m5C-seq) to analyze m5C modifications.
- Conjoint analysis of scRNA-seq and m5C-seq data.
- In vivo studies using nanoparticle-delivered siRNA in SLE mouse models.
Main Results:
- A distinct CD7highCD74high CD8+T cell subgroup with exhausted features was identified in SLE patients, showing diagnostic value.
- NSUN4 was identified as a key regulator in SLE pathogenesis.
- NSUN4 knockdown reduced CD74 expression, m5C levels, and CD8+T cell exhaustion via CD44/mTOR-mediated mitophagy.
- Targeting NSUN4 with siRNA reduced autoimmune kidney damage in SLE mouse models.
Conclusions:
- An exhausted CD7highCD74high CD8+T cell subset plays a significant role in SLE.
- NSUN4-mediated regulation of CD74 and mitophagy is crucial in SLE pathogenesis.
- Targeting NSUN4 presents a potential therapeutic strategy for SLE.
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