Abstract
BACKGROUND: Rheumatoid arthritis (RA) is a prevalent chronic autoimmune disease. While the chemokine signaling pathway plays a pivotal role in RA pathogenesis, the specific cellular interactions remain unclear. METHODS: A three-stage analytical framework was implemented. First, to uncover crucial signaling pathways in RA, we conducted an analysis of bulk RNA-seq data (GSE89408) sourced from the Gene Expression Omnibus (GEO) database. Second, utilizing single-cell transcriptome data from GEO (GSE200815 and GSE152805) and EMBL's European Bioinformatics Institute (E-MTAB-8322), we delved into key cell pairs and their ligand-receptor interactions within the chemokine signaling pathway. Third, spatial transcriptome data (SDY2213) from the IMMPORT database were employed to validate the colocalization of these pivotal cell pairs. RESULTS: Our enrichment analysis of bulk RNA-seq data underscored the chemokine signaling pathway's centrality in RA's pathogenesis. By integrating thirteen single-cell RNA sequencing datasets, we documented a notable elevation in the proportion of most lymphocyte types within RA synovium. The chemokine signaling pathway emerged as one of the primary pathways enriched in genes differentially expressed between RA and osteoarthritis in lymphocytes and CD8(+) T cells. Cell-cell interaction analysis pinpointed the interaction between CD8(+) T cells and endothelial cells (ECs) as a distinctive feature of the chemokine signaling pathway. Spatial transcriptome analysis further substantiated the co-localization of CD8(+) T cells and ECs. CONCLUSIONS: This study highlight CD8(+) T cell- EC interactions via chemokine signaling as critical drivers of RA progression, potentially promoting leukocyte transendothelial migration and synovial immune infiltration.