Abstract
OBJECTIVES: Recent research has highlighted the critical role of monocytes and macrophages in driving both inflammatory and fibrotic processes in systemic sclerosis. This study seeks to elucidate the gene expression profiles of systemic sclerosis monocytes and their potential links to disease complications, with the ultimate goal of uncovering novel therapeutic targets. METHODS: A total of 48 systemic sclerosis patients and 15 controls were recruited and monocytes were isolated using CD14+ magnetic beads. Total RNA was extracted and bulk RNA-seq analysis was performed. Differential gene expression followed by unsupervised hierarchical clustering and pathway analysis was conducted, and correlations with clinical features were analyzed. Interferon signature score (IFN6) was calculated using the log transformed values of six genes (IFIT3, IFIT2, MX1, IFIH1, STAT2, and NCF1). RESULTS: We identified four distinct patient subgroups, relative to normal, two with inflammatory and two with non-inflammatory gene profiles. The inflammatory subgroups exhibited high expression of interferon-related genes and included all systemic sclerosis patients with pulmonary hypertension and most with cardiac involvement. In these patients, IFN6 was markedly elevated and showed a significant correlation with global longitudinal strain (GLS; r = -0.5, p = 0.006), a key indicator of cardiac function. Furthermore, pathway analysis identified an enrichment of the Notch signaling pathway among genes whose overexpression correlated with impaired global longitudinal strain. CONCLUSION: These findings unveil a potential new mechanistic link between interferon activity, Notch signaling, and cardiac complications in systemic sclerosis, offering new insights into disease pathogenesis and potential therapeutic targets.