Distinct metabolic profiles of circulating plasmacytoid dendritic cells in systemic sclerosis patients stratified by clinical phenotypes

BackgroundPlasmacytoid dendritic cells (pDCs) play a key role in systemic sclerosis (SSc) pathophysiology. However, despite the recognised importance of metabolic reprogramming for pDC function, their metabolic profile in SSc remains to be elucidated. Thus, our study aimed to investigate the role of pDC metabolism in SSc. MethodsPeripheral blood mononuclear cells (PBMCs) were isolated from the blood of healthy donors and SSc patients. SCENITH, a single-cell flow cytometry-based method, was applied to infer the metabolic profile of circulating pDCs from patients with SSc. pDCs (CD304+ Lin-) at steady-state or stimulated with CpG A were analysed. Toll-like receptor (TLR)9 activation was confirmed by ribosomal protein S6 phosphorylation. ResultsCirculating pDCs from 10 healthy donors and 14 SSc patients were analysed. pDCs from anti-centromere antibody-positive (ACA+) patients displayed higher mitochondrial dependence and lower glycolytic capacity than those from anti-topoisomerase I antibody- positive (ATA+) patients. Furthermore, cells from both ACA+ patients and limited cutaneous SSc (lcSSc) patients showed a stronger response towards TLR9 activation than cells from ATA+, anti-RNA polymerase III antibody-positive (ARA+) or diffuse cutaneous SSc (dcSSc) patients. ConclusionsOur results show that pDCs from ACA+ patients rely more on oxidative phosphorylation (OXPHOS) and are more responsive to external stimuli, suggesting that pDCs from ATA+ patients may be more activated or exhausted. These findings point for the possible contribution of pDC metabolism to SSc clinical course, unveiling new potential targets for therapeutic approaches in SSc.