Neutrophil Extracellular Traps Induce Pyroptosis of Rheumatoid Arthritis Fibroblast-Like Synoviocytes via the NF-κB/Caspase 3/GSDME Pathway

Jing Mao; Min Tan; Jun Li; Chunhua Liu; Jiayao Hao; Jianxiong Zheng; Haili Shen

doi:10.1007/s10753-023-01951-x

Neutrophil Extracellular Traps Induce Pyroptosis of Rheumatoid Arthritis Fibroblast-Like Synoviocytes via the NF-κB/Caspase 3/GSDME Pathway

Inflammation. 2023 Dec 22. doi: 10.1007/s10753-023-01951-x. Online ahead of print.

Authors

Jing Mao^{1

2}, Min Tan^{1

2}, Jun Li^{1

2}, Chunhua Liu^{1

2}, Jiayao Hao^{1

2}, Jianxiong Zheng^{1

2}, Haili Shen³

Affiliations

¹ Department of Rheumatology, Lanzhou University Second Hospital, Lanzhou, Gansu, 730000, China.
² The Second Clinical Medical College, Lanzhou University, Lanzhou, Gansu, 730000, China.
³ Department of Rheumatology, Lanzhou University Second Hospital, Lanzhou, Gansu, 730000, China. shenhl@lzu.edu.cn.

PMID: 38133702
DOI: 10.1007/s10753-023-01951-x

Abstract

Rheumatoid arthritis (RA) is an enduring, progressive autoimmune disorder. Abnormal activation of fibroblast-like synoviocytes (FLSs) has been proposed as the initiating factor for inflammation of the synovium and bone destruction. Neutrophil extracellular traps (NETs), which are web-like structures composed of DNA, histones, and granule proteins, are involved in the development of RA in multiple aspects. Pyroptosis, gasdermin-mediated inflammatory programmed cell death, plays a vital function in the etiopathogenesis of RA. However, the exact mechanism underlying NETs-induced pyroptosis in FLSs of RA and its impact on cellular pathogenic behavior remain undefined. In this study, we demonstrated that gasdermin E (GSDME) expression was upregulated in RA plasma and synoviums, which was positively correlated with the elevated cell-free DNA (cfDNA) and citrullinated histone 3 (Cit H3) levels in the plasma. Additionally, in vitro experiments have shown that NETs triggered caspase 3/GSDME-mediated pyroptosis in RA-FLSs, characterized by decreased cell viability, cell membrane blebbing, and rupture, as well as increased levels of pyroptosis-related proteins and pro-inflammatory cytokines. Again, silencing GSDME significantly inhibited pyroptosis and suppressed the migration, invasion, and secretion of pro-inflammatory cytokines in RA-FLSs. Furthermore, we also found that the nuclear factor-kappa B (NF-κB) pathway, serving as an upstream mechanism, was involved in FLS pyroptosis. In conclusion, our investigation indicated that NETs could induce RA-FLS pyroptosis and facilitate phenotypic transformation through targeting the NF-κB/caspase 3/GSDME axis. This is the first to explore the crucial role of NETs-induced FLS pyroptosis in the progression of RA, providing novel targets for the clinical management of refractory RA.

Keywords: fibroblast-like synoviocytes; gasdermin E.; neutrophil extracellular traps; pyroptosis; rheumatoid arthritis.