title: Succinate/NLRP3 Inflammasome Induces Synovial Fibroblast Activation: Therapeutical Effects of Clematichinenoside AR on Arthritis.
abstract: Clematichinenoside AR (C-AR) is a triterpene saponin isolated from the root ofClematis manshuricaRupr., which is a herbal medicine used in traditional Chinese medicine for the treatment of arthritis. C-AR exerts anti-inflammatory and immunosuppressive properties, but little is known about its action in the suppression of fibroblast activation. Low oxygen tension and transforming growth factor-β (TGF-β1) induction in the synovium contribute to fibrosis in arthritis. This study was designed to investigate the effect of C-AR on synovial fibrosis from the aspects of hypoxic TGF-β1 and hypoxia-inducible transcription factor-1α (HIF-1α) induction. In the synovium of rheumatoid arthritis (RA) rats, hypoxic TGF-β1 induction increased succinate accumulation due to the reversal of succinate dehydrogenase (SDH) activation and induced NLRP3 inflammasome activation in a manner dependent on HIF-1α induction. In response to NLRP3 inflammasome activation, the released IL-1β further increased TGF-β1 induction, suggesting the forward cycle between inflammation and fibrosis in myofibroblast activation. In the synovium of RA rats, C-AR inhibited hypoxic TGF-β1 induction and suppressed succinate-associated NLRP3 inflammasome activation by inhibiting SDH activity, and thereby prevented myofibroblast activation by blocking the cross-talk between inflammation and fibrosis. Taken together, these results showed that succinate worked as a metabolic signaling, linking inflammation with fibrosis through NLRP3 inflammasome activation. These findings suggested that synovial succinate accumulation and HIF-1α induction might be therapeutical targets for the prevention of fibrosis in arthritis.
authors.affiliation: State Key Laboratory of Natural Medicines, Department of Chinese Medicines Analysis, China Pharmaceutical University , Nanjing , China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Li
authors.affiliation: State Key Laboratory of Natural Medicines, Department of Chinese Medicines Analysis, China Pharmaceutical University , Nanjing , China.
authors.forename: Jia-Yi
authors.initials: JY
authors.lastname: Zheng
authors.affiliation: Key Laboratory of Modern Preparation of TCM, Ministry of Education, Jiangxi University of Traditional Chinese Medicine , Nanchang , China.
authors.forename: Jian-Qun
authors.initials: JQ
authors.lastname: Liu
authors.affiliation: State Key Laboratory of Natural Medicines, Department of Chinese Medicines Analysis, China Pharmaceutical University , Nanjing , China.
authors.forename: Jie
authors.initials: J
authors.lastname: Yang
authors.affiliation: State Key Laboratory of Natural Medicines, Department of Chinese Medicines Analysis, China Pharmaceutical University , Nanjing , China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Liu
authors.affiliation: State Key Laboratory of Natural Medicines, Department of Chinese Medicines Analysis, China Pharmaceutical University , Nanjing , China.
authors.forename: Chen
authors.initials: C
authors.lastname: Wang
authors.affiliation: Cellular and Molecular Biology Center of China Pharmaceutical University , Nanjing , China.
authors.forename: Xiao-Nan
authors.initials: XN
authors.lastname: Ma
authors.affiliation: State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of TCM Evaluation and Translational Research, Department of Complex Prescription of TCM, China Pharmaceutical University , Nanjing , China.
authors.forename: Bao-Lin
authors.initials: BL
authors.lastname: Liu
authors.affiliation: State Key Laboratory of Natural Medicines, Department of Chinese Medicines Analysis, China Pharmaceutical University , Nanjing , China.
authors.forename: Gui-Zhong
authors.initials: GZ
authors.lastname: Xin
authors.affiliation: State Key Laboratory of Natural Medicines, Department of Chinese Medicines Analysis, China Pharmaceutical University , Nanjing , China.
authors.forename: Li-Fang
authors.initials: LF
authors.lastname: Liu
keywords: HIF-1α; NLRP3 inflammasome; TGF-β1; clematichinenoside AR; collagen-induced arthritis; succinate; synovial fibrosis