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TLR3 as an emerging molecule facilitating pyroptosis in the context of rheumatoid arthritis: A study combined
Meng-Yuan Zhou1, Hong-Yan Feng1, Tian-Tian Wang2
1Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, School of Pharmacy, Anhui Medical University, Hefei 230032, Anhui Province, China.
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.
Insights
This study identifies novel pyroptosis-related genes in rheumatoid arthritis (RA), finding that high TLR3 expression promotes joint inflammation and disease progression, suggesting TLR3 as a potential diagnostic marker and therapeutic target for RA.
Area of Science:
- Immunology
- Molecular Biology
- Rheumatology
Background:
- Rheumatoid arthritis (RA) is an immune-mediated inflammatory joint disease.
- Pyroptosis, an immune-related cell death, plays a role in RA pathogenesis but requires further elucidation.
- This research aimed to identify novel pyroptosis-related markers and understand their functional significance in RA.
Purpose of the Study:
- To identify crucial pyroptosis-related genes (DEPRGs) in rheumatoid arthritis (RA).
- To investigate the role of these genes in RA pathogenesis and immune cell infiltration.
- To screen for potential therapeutic targets and drugs for RA.
Main Methods:
- Utilized GEO database for DEPRG identification in RA.
- Performed enrichment analysis, PPI network, WGCNA, and CIBERSORT for hub gene screening and immune cell analysis.
- Conducted validation experiments to confirm gene expression, regulatory roles, and screened potential drugs.
Main Results:
- Identified 46 DEPRGs involved in NOD-like receptor and Toll-like receptor signaling pathways.
- Discovered CCL5, LY96, and TLR3 as crucial hub genes with increased expression in RA synovial tissue and FLS.
- Knocking down TLR3 inhibited RA FLS hyperproliferation and pyroptosis; dexamethasone and doxorubicin showed potential therapeutic effects by inhibiting TLR3.
Conclusions:
- High expression of TLR3 promotes FLS pyroptosis and RA progression.
- TLR3 is a potential diagnostic biomarker for RA.
- TLR3 represents a promising therapeutic target for RA treatment.
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