Endothelial response to type I interferon contributes to vasculopathy and fibrosis and predicts disease progression of systemic sclerosis

BACKGROUND/PURPOSE: Type I interferon (IFN-1) signatures are a hallmark of patients with systemic sclerosis (SSc). However, its significance in clinical stratification and contribution to deterioration still need to be better understood. METHODS: For hypothesis generation, we performed single-cell RNA sequencing (scRNAseq) on skin biopsies (SSc=4, control =2) using the BD Rhapsody platform. Two publicly available datasets of skin scRNAseq were used for validation (GSE138669: dcSSc=12, control=10; GSE195452: dcSSc=52, lcSSc=41, control =54). The IFN-1 signature was mapped, functionally investigated in a bleomycin plus IFNα2-adeno-associated virus (IFNA2-AAV) induced model, and verified in an SSc cohort (n=61). RESULTS: The discovery and validation datasets showed similar findings. Endothelial cells (EC) had the most prominent IFN-1 signature among dermal non-immune cells. The EC IFN-1 signature was increased both in SSc vs. controls and in dcSSc vs. lcSSc. Among EC subclusters, the IFN-1 signature was statistically higher in HC< lcSSc