Circulating classical monocytes share a common transcriptional signature with skin macrophages in Systemic Sclerosis

Abstract

Abstract The etiology and pathogenesis of systemic sclerosis (SSc) are poorly understood. Circulating monocytes likely play a critical role in SSc progression through secretion of proinflammatory molecules and as precursors of macrophages that can reorganize the extracellular matrix, thereby leading to development of end-organ fibrosis. Here, we evaluate the transcriptional similarities between circulating classical monocytes (CMo) and skin macrophages of SSc patients. Bulk RNA-seq was performed on sorted CMo from SSc blood obtained through the Prospective Registry of Early Systemic Sclerosis (PRESS) cohort, and transcriptional profiles were analyzed along with profiles from matched control samples. Additionally, sorted CD45+ cells from skin biopsies of one SSc patient and one control patient were prepared for single-cell RNA-seq. There was a numerical expansion of skin macrophages from the control to the SSc sample, but no significant difference in the quantity of circulating CMo between control and SSc patients. Of the 152 significantly upregulated genes (DESeq2, p<0.05, fold change>2) observed in circulating CMo population and the 290 upregulated genes (fold change>2) in the skin macrophage cluster compared to their respective controls, we found 23 genes in common (p<1.23×10−8, hypergeometric distribution test). These shared genes were involved in various immune and inflammatory regulation processes. These data indicate that a common transcriptional signature may exist between circulating CMo and macrophages present in the skin of SSc patients, potentially suggesting that macrophage-specific pathways at the site of fibrosis can be detected in a circulating precursor population.