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

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. For hypothesis generation, we performed single-cell RNA sequencing (scRNAseq) on skin biopsies (SSc=4, control =2) using the BD Rhapsody platform. The IFN-1 signature was mapped, functionally investigated in a bleomycin plus IFNa2-adeno-associated virus (IFNA2-AAV) induced model, and verified in an SSc cohort (n=61). 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. IFNA2-AAV deteriorated bleomycin-induced dermal fibrosis, EndoMT, and perivascular fibrosis and caused blood vessel loss with EC apoptosis. Vascular MX1, an IFN-1 response protein, was significantly increased both in total SSc skin vs. healthy controls and in dcSSc vs. lcSSc. Baseline vascular MX1 performed similarly to skin score in predicting disease progression over 6-34 months in total SSc and was superior in the dcSSc subpopulation. To sum up, the EC IFN-1 signature distinguished SSc skin subtypes and disease progression and may contribute to vasculopathy and fibrosis. Overall design: Distal forearm skin from 2 healthy volunteers, 1 patient with diffuse cutaneous systemic sclerosis (dcSSc) and 3 patients with limited cutaneous systemic sclerosis (lcSSc)