AUTHOR=Zhang Runrun , Jin Yehua , Chang Cen , Xu Lingxia , Bian Yanqin , Shen Yu , Sun Yang , Sun Songtao , Schrodi Steven J. , Guo Shicheng , He Dongyi 

TITLE=RNA-seq and Network Analysis Reveal Unique Chemokine Activity Signatures in the Synovial Tissue of Patients With Rheumatoid Arthritis

JOURNAL=Frontiers in Medicine

VOLUME=Volume 9 - 2022

YEAR=2022

URL=https://www.frontiersin.org/journals/medicine/articles/10.3389/fmed.2022.799440

DOI=10.3389/fmed.2022.799440

ISSN=2296-858X

ABSTRACT=Purpose: This study aimed to provide a comprehensive understanding of the genome-wide expression patterns in synovial tissue samples of patients with rheumatoid arthritis (RA) to investigate the potential mechanisms regulating RA occurrence and development. Methods: Transcription profiles of synovial tissue samples from nine RA patients and 15 osteoarthritis (OA; control) patients from the East Asian population were generated using RNA sequencing. Gene set enrichment analysis (GSEA) was used to analyze all detected genes, and differentially expressed genes (DEGs) were identified using DESeq. To further analyze the DEGs,GO  enrichment and KEGG pathway analyses were performed. The protein–protein interaction (PPI) network of DEGs was constructed using STRING, and the hub genes were identified by topology clustering with MCODE-Cytoscape. The most important hub genes were validated using qRT-PCR. Results: Of the 17,736 genes detected, 851 were identified as DEGs (474 upregulated and 377 downregulated genes) using the false discovery rate (FDR) approach. GSEA revealed that the significantly enriched gene sets that positively correlated with RA were CD40 signaling over-activation, Th1 cytotoxic module, over-activation of immune response, adaptive immune response, effective versus memory CD8 T cells (upregulated), and naïve versus effective CD8 T cells (downregulated). Biological process enrichment analysis showed that the DEGs were significantly enriched for signal transduction, immune response, and inflammatory response . Molecule function enrichment analysis revealed that the DEGs were enriched in calcium ion binding, receptor binding, and cytokine activity. Cellular component enrichment analysis revealed that the DEGs were significantly enriched in the plasma membrane, integral component of membrane, and extracellular region. KEGG pathway analysis showed that the DEGs were enriched in the cytokine-cytokine receptor interaction, chemokine signaling, T cell receptor signaling, and RA pathways. We confirmed that RA was correlated with the upregulation of the PPI network hub genes CXCL13, CXCL6, CCR5, CXCR5, CCR2, CXCL3, and CXCL10, and the downregulation of the hub gene SSTR1. Conclusions: This study identified and validated DEGs in synovial tissue samples of RA patients, which highlighted the activity of a subset of chemokine genes, thereby providing novel insights into the molecular mechanisms of RA pathogenesis and identifying potential diagnostic and therapeutic targets for RA.