Succinate/NLRP3 Inflammasome Induces Synovial Fibroblast Activation: Therapeutical Effects of Clematichinenoside AR on Arthritis.

Yi Li,Jie Yang,Jia-Yi Zheng,Gui-Zhong Xin,Xiao-Nan Ma,Li-Fang Liu,Jian-Qun Liu,Bao-Lin Liu,Chen Wang,Yang Liu

doi:10.3389/fimmu.2016.00532

Abstract

Clematichinenoside AR (C-AR) is a triterpene saponin isolated from the root of Clematis manshurica Rupr., 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.

Highlights

Rheumatoid arthritis (RA) is an inflammatory autoimmune disease characterized by hyperplasia of the synovial membranes and progressive destruction of cartilage and bone with impaired joint function
We demonstrated that IL-1βmediated inflammation led to fibroblast activation through TGFβ1 induction, which further stimulated IL-1β production for the persistent fibroblast activation
Succinate accumulation acted as a metabolic signaling linking IL-1β and TGF-β1 induction in the ahead cycle, establishing the cross-talk between inflammation and fibrosis and further exacerbating tissue injury in rheumatoid arthritis (RA)

Summary

Introduction

Rheumatoid arthritis (RA) is an inflammatory autoimmune disease characterized by hyperplasia of the synovial membranes and progressive destruction of cartilage and bone with impaired joint function. In RA, fibroblast activation and extracellular matrix (ECM) remodeling are key events responsible for synovial tissue fibrosis [1, 2]. TGF-β1 Induces Succinate/NLRP3 Inflammasome Activation functions involved in the regulation of cell differentiation, tissue proliferation, and fibrogenesis. Similar to the action in diabetic nephropathy [5], pulmonary fibrosis [6], and liver fibrosis [7], TGF-β1 levels are elevated in the synovial fluid of arthritis patients, correlating with up-regulated genes involved in ECM turnover [8]. Aberrant activation of TGF-β1 is observed in RA rats, and responsible for joint destruction [9]. These events indicate that TGF-β1 is the control mediator in fibrogenesis

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Conclusion