Proteasome defects in candle patients’ cells lead to IFN production in both hemopoietic and non-hemopoietic cells (INM6P.416)

CANDLE (Chronic Atypical Neutrophilic Dermatosis with Lipodystrophy and Elevated Temperature) syndrome is an autoinflammatory disease caused by autosomal recessive mutations in PSMB8 and other subunits of the proteasome. Many IFN regulated genes in CANDLE patients’ whole blood were strongly upregulated and patient monocytes showed STAT1 hyperactivation after IFN-γ stimulation. We hypothesized that cellular stress in CANDLE patients leads to IFN production and asked whether it is restricted to hematopoietic cells. We studied IFN production in PBMCs and fibroblasts from CANDLE patients or in healthy cells treated with proteasome inhibitor epoxomicin. We found increased production of IFN-α and IFN-γ in NK, T and dendritic cells from the two CANDLE patients tested compared with healthy controls. Increased IFN production was reproduced in PBMCs of healthy individuals treated with epoxomicin. We also observed increased IFN-α message in CANDLE patients’ fibroblasts compared to healthy controls. Similarly, epoxomicin treated healthy fibroblasts increased IFN-α message. Interestingly message for other inflammatory cytokines, including TNF-α, IL-1 and IL-6, were either not change or even suppressed. Microarray study showed that IFN regulated genes were upregulated in sorted T, B, NK cells, monocytes and neutrophils. We conclude that proteasome defect causes IFN production in both hemopoietic and non-hemopoietic cells in CANDLE patients that can lead to increased IFN signaling.