In:
Arthritis & Rheumatology, Wiley
Abstract:
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 〈 dcSSc capillary ECs. Endothelial‐to‐mesenchymal transition (EndoMT) scores increased in parallel. 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. Conclusion The EC IFN‐1 signature distinguished SSc skin subtypes and disease progression and may contribute to vasculopathy and fibrosis. image
Type of Medium:
Online Resource
ISSN:
2326-5191
,
2326-5205
Language:
English
Publisher:
Wiley
Publication Date:
2023
detail.hit.zdb_id:
2754614-7
Permalink