STAT3 Signaling Contributes to Chemokine Production in E2-Induced Dermal Inflammation

Scleroderma (SSc) is characterized by dermal inflammation and fibrosis. Patients with SSc have elevated circulating levels of estradiol (E2) that contribute to dermal fibrosis. Using bulk RNA sequencing (RNA-seq), we investigated inflammatory pathways in E2 or ethanol (ETOH, vehicle)-treated human skin tissue for 48 h to identify differentially expressed genes (DEGs) and enriched pathways. Among the 90 DEGs responsive to E2 treatment, many were associated with enriched inflammatory pathways. Likewise, cytokine and chemokine activities were among the most significantly enriched molecular function terms. qPCR and protein analyses demonstrated increased cytokine and chemokine expression in primary dermal fibroblasts. CIBERSORTx deconvolution using a skin single-cell reference suggested an activated fibroblast transcriptional signature in E2-treated human skin tissue. In this tissue, E2-induced IL-6 and CXCL8 transcript levels were positively correlated. Pharmacologic STAT3 inhibition reduced E2-induced CXCL2, CXCL3, CXCL8, and CCL20 transcript levels in human skin tissue. In SSc dermal fibroblasts, anastrozole treatment significantly decreased CXCL3 and CXCL8 transcript levels. Together, these data suggest that E2 contributes, in part, to increased CXCL2, CXCL3, CXCL8, and CCL20 transcripts and that IL-6/STAT3 signaling may be important in this dermal inflammatory response.