Gasdermin-E Mediated Pyroptosis-A Novel Mechanism Regulating Migration, Invasion and Release of Inflammatory Cytokines in Rheumatoid Arthritis Fibroblast-like Synoviocytes.

Tao Wu,Jian-Da Ma,Le-Feng Chen,Lie Dai,Yao-Wei Zou,Ruo-Fan Ma,Xue-Pei Zhang,Yao-Yao Zou,Zhong Chen,Ji-Meng Xue,Qian Zhang

doi:10.3389/fcell.2021.810635

Abstract

Synovium fibroblast-like synoviocytes (FLSs) are important participants in the pathogenesis of synovitis and joint destruction in rheumatoid arthritis (RA). Pyroptosis is a pro-inflammatory and cell lytic programmed cell death mechanism mediated by gasdermin (GSDM) family proteins. In this study, we demonstrated the increased expression of GSDME and increased levels of GSDME-mediated pyroptosis in RA synovial tissues. In vitro, stimulation with TNF-α plus hypoxia mimicking the inflammatory and hypoxic environment in RA synovium induced GSDME-mediated pyroptosis in RA-FLSs in combination with the promotion of migration and invasion abilities and the release of inflammatory cytokines (IL-6, IL-8). Moreover, knockdown of GSDME significantly inhibited the proliferation rate, migration/invasion effects and cytokines released through the reduction of GSDME-mediated pyroptosis. The immunohistochemistry results showed that RA patients with high GSDME N-terminal (GSDME-NT) expression, which is the active form of GSDME, showed higher IL-6 expression in both lining and sublining layer of synovium than that in patients with low GSDME-NT expression, osteoarthritis and non-inflammatory orthopedic arthropathies. Our findings revealed a novel mechanism regulating cell proliferation, migration, invasion and inflammatory cytokines release during the process of GSDME mediated pyroptosis in RA.

Highlights

Rheumatoid arthritis (RA) is an autoimmune disease characterized by chronic synovitis accompanied by excessive release of inflammatory cytokines and the destruction of bone and cartilage
Weighted correlation network analysis (WGCNA) showed that GSDME was annotated against THY1(+) fibroblast cell population (Supplementary Figure S1B), which was found to be remarkably expanded in rheumatoid arthritis (RA) synovium compared to control synovium and correlated with severe and persistent inflammation in RA (Croft et al, 2019; Wei et al, 2020)
GSDME-NT and GSDME-FL expression was significantly increased in synovium extracts from RA patients compared to those from Orth.A patients, but statistic difference was not found in either GSDME-FL or GSDME-NT levels between OA synovium and Orth.A synovium (Figure 1B, Supplementary Figure S2)

Summary

Introduction

Rheumatoid arthritis (RA) is an autoimmune disease characterized by chronic synovitis accompanied by excessive release of inflammatory cytokines and the destruction of bone and cartilage. Increasing researches have been concentrated on the mechanisms underlying the abnormal proinflammatory responses and invasive behaviors of RA-FLSs and, hopefully, possible treatment strategies based on targeting RA-FLSs. Pyroptosis is a form of programmed cell death featuring cell swelling and large bubbles blowing from the plasma membrane mediated by pore-forming gasdermin (GSDM) family proteins (Shi et al, 2017). Pyroptosis is a proinflammatory process because of its cell lytic activity, which mediates excessive release of inflammatory mediators and induces and aggravates inflammation (Shi et al, 2017). Based on this feature, pyroptosis might play a crucial role in the genesis and development of RA. We illuminated the role of GSDME-mediated FLSs pyroptosis in RA, providing a novel insight for the mechanisms of inflammatory cytokines secretion and aggressive cell behaviors in RA-FLSs

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Results

Conclusion