TLR3 as an emerging molecule facilitating pyroptosis in the context of rheumatoid arthritis: A study combined bioinformatics and experimental validation
Meng-yuan Zhou , Hong-yan Feng , Tian-tian Wang , Ze-shan Xu , Sheng-long Gu , Ling-ling Li , Li Cai , Rong Li
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Abstract
Background
Rheumatoid arthritis (RA) is an inflammatory disease of the joints mediated by immune cells. As an immune-related mode of cell death, pyroptosis has yet to be fully understood in RA. This research identified novel pyroptosis-related markers in RA and confirmed its functional significance in RA.
Methods
Initially, crucial pyroptosis-related genes of RA were identified through GEO database, and biological pathways were determined through enrichment analysis. Then, PPI network, WGCNA and CIBERSORT analysis was utilized to screen hub genes and evaluate immune cell infiltration levels. Finally, validation experiments determined hub genes expression and regulatory roles in RA pathogenesis, and screened potential therapeutic drugs.
Results
A total of 46 DEPRGs in RA were identified, which involved in NOD-like receptor and Toll-like receptor signaling pathway. Further screening revealed 3 crucial hub genes: CCL5, LY96, and TLR3 had significantly increased expression in RA synovial tissue and FLS, which might become diagnostic markers of RA. Analysis of immune infiltration revealed that hub genes exhibited associations with plasma cells, T lymphocytes, and macrophages. Further study on the crucial hub gene TLR3 revealed that knocking down TLR3 significantly inhibited the RA FLS hyperproliferation and pyroptosis, and dexamethasone and doxorubicin, as potential drugs, could treat RA by inhibiting TLR3.
Conclusion
Our study indicates that high expression of TLR3 promotes FLS pyroptosis and RA progression, suggesting its potential as both a biomarker and a therapeutic target for RA.
期刊介绍：
The journal Cytokine has an open access mirror journal Cytokine: X, sharing the same aims and scope, editorial team, submission system and rigorous peer review.
* Devoted exclusively to the study of the molecular biology, genetics, biochemistry, immunology, genome-wide association studies, pathobiology, diagnostic and clinical applications of all known interleukins, hematopoietic factors, growth factors, cytotoxins, interferons, new cytokines, and chemokines, Cytokine provides comprehensive coverage of cytokines and their mechanisms of actions, 12 times a year by publishing original high quality refereed scientific papers from prominent investigators in both the academic and industrial sectors.
We will publish 3 major types of manuscripts:
1) Original manuscripts describing research results.
2) Basic and clinical reviews describing cytokine actions and regulation.
3) Short commentaries/perspectives on recently published aspects of cytokines, pathogenesis and clinical results.
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