The key celltype mediated by type I interferon-stimulated genes in systemic lupus erythematosus revealed by single-cell and bulk RNA- seq analysis

Abstract

Background Systemic lupus erythematosus (SLE) is a complex autoimmune disease. Type I interferon (IFN-I) is one of the key pathogenic mechanisms, and overexpression of IFN-I leads to enhanced expression of its downstream interferon-stimulated genes (ISGs) and causes aberrant autoimmune responses. To date, a comprehensive assessment of ISG-mediated cell subsets in SLE remains lacking. Methods We analyzed single-cell transcriptomics data from peripheral blood mononuclear cells (PBMC) of seven SLE patients and five healthy individuals and retrieved 193 interferon-stimulated genes (ISGs) from the MSigDB database. Then, we performed the non-negative matrix factorization to identify different ISG-associated cellular subpopulations based on cellular ISG expression profiles and performed pseudotime trajectory analysis, differentially expressed gene (DEG) analysis, pathway enrichment analyses, transcription factor activity analyses, and cellular communication analyses on key cellular subpopulations. Bulk RNA-sequencing data from SLE also elucidated correlation of ISG-mediated microenvironmental patterns with other immune pathways. Results We find significantly higher proportions of CD8 T cells, NKT cells and monocytes and lower proportions of CD4 T cells and B cells. The CD8 T_ISG15, CD4 T_ISG15, NK_ISG15, NKT_ISG15, B_ISG15, and cDC_ISG15 subpopulations are significantly enriched for differential genes in the interferon-signalling-related pathway and had high expression of immune checkpoints, such as HLA-DRB5. In addition, we observe significantly higher activity of transcription factors, such as STAT1 and IRF7. Combined with bulk RNA-seq data, we find that the ISGs feature scores of each cell subpopulation are correlated with the immune-related pathway scores and HLA gene expression significantly in several datasets. In addition, ISG-mediated cell subtypes enhance intercellular communication. Conclusion This study comprehensively reveals that ISGs are highly expressed in key cell subpopulations of SLE and are closely associated with disease activity. These findings emphasize the central role of type I interferon-stimulated genes in SLE immunomodulation and disease progression, providing an important basis for precision therapy.