TNF antagonist sensitizes synovial fibroblasts to ferroptotic cell death in collagen-induced arthritis mouse models

Expansion of synovial fibroblast is associated with rheumatoid arthritis (RA) progression, but how this expansion is regulated is still not clear. Here the authors use a mouse RA model, single cell RNA sequencing and in vitro analyses to show that inducing ferroptosis and suppressing TNF signaling reduce fibroblast numbers and ameliorate experimental arthritis. Ferroptosis is a nonapoptotic cell death process that requires cellular iron and the accumulation of lipid peroxides. In progressive rheumatoid arthritis (RA), synovial fibroblasts proliferate abnormally in the presence of reactive oxygen species (ROS) and elevated lipid oxidation. Here we show, using a collagen-induced arthritis (CIA) mouse model, that imidazole ketone erastin (IKE), a ferroptosis inducer, decreases fibroblast numbers in the synovium. Data from single-cell RNA sequencing further identify two groups of fibroblasts that have distinct susceptibility to IKE-induced ferroptosis, with the ferroptosis-resistant fibroblasts associated with an increased TNF-related transcriptome. Mechanistically, TNF signaling promotes cystine uptake and biosynthesis of glutathione (GSH) to protect fibroblasts from ferroptosis. Lastly, low dose IKE together with etanercept, a TNF antagonist, induce ferroptosis in fibroblasts and attenuate arthritis progression in the CIA model. Our results thus imply that the combination of TNF inhibitors and ferroptosis inducers may serve as a potential candidate for RA therapy.

Automated summary

In this study, the authors use a mouse model of rheumatoid arthritis (RA) and single-cell RNA sequencing to show that inducing ferroptosis and suppressing TNF signaling can reduce the number of fibroblasts in the synovium and improve experimental arthritis. They further identify two groups of fibroblasts with distinct susceptibility to ferroptosis and show that TNF signaling protects fibroblasts from ferroptosis through promoting cystine uptake and glutathione biosynthesis. Finally, the combination of low-dose ferroptosis inducer and TNF antagonist attenuates arthritis progression in the mouse model.