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

Jiao Wu (), Zhuan Feng, Liang Chen, Yong Li, Huijie Bian, Jiejie Geng, Zhao-Hui Zheng, Xianghui Fu, Zhuo Pei, Yifei Qin, Liu Yang, Yilin Zhao, Ke Wang, Ruo Chen, Qian He, Gang Nan, Xuejun Jiang (), Zhi-Nan Chen () and Ping Zhu ()
Additional contact information
Jiao Wu: Xijing Hospital, Fourth Military Medical University
Zhuan Feng: Fourth Military Medical University
Liang Chen: Shanghai University
Yong Li: Fourth Military Medical University
Huijie Bian: Fourth Military Medical University
Jiejie Geng: Fourth Military Medical University
Zhao-Hui Zheng: Xijing Hospital, Fourth Military Medical University
Xianghui Fu: Xijing Hospital, Fourth Military Medical University
Zhuo Pei: Fourth Military Medical University
Yifei Qin: Fourth Military Medical University
Liu Yang: Fourth Military Medical University
Yilin Zhao: Xijing Hospital, Fourth Military Medical University
Ke Wang: Fourth Military Medical University
Ruo Chen: Fourth Military Medical University
Qian He: Fourth Military Medical University
Gang Nan: Fourth Military Medical University
Xuejun Jiang: Memorial Sloan-Kettering Cancer Center
Zhi-Nan Chen: Fourth Military Medical University
Ping Zhu: Xijing Hospital, Fourth Military Medical University

Nature Communications, 2022, vol. 13, issue 1, 1-16

Abstract: Abstract 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.

Date: 2022
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DOI: 10.1038/s41467-021-27948-4

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