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SLC7A11 suppresses pyroptosis to alleviate rheumatoid arthritis development by modulating the IL-17 pathway
Shaojian Chen1, Longqiang Zou1, Liangcai Huang1
1Department of Sports Medical Ganzhou People's Hospital/The Affiliated Ganzhou Hospital Jiangxi Medical College Nanchang University Ganzhou China.
Background:
Rheumatoid arthritis (RA) is an autoimmune disease of unknown etiology. This study aims to explore the potential mechanisms by which solute carrier family 7 member 11 (SLC7A11) influences RA development.
Methods:
Collagen-induced arthritis (CIA) mice were constructed to observe disease onset and pathological scores. Pathological changes were examined using Hematoxylin-eosin and Safranin O-Fast Green staining. Levels of lactate dehydrogenase (LDH), inflammatory cytokines (tumor necrosis factor [TNF]-α, interleukin [IL]-18 and IL-1β), and oxidative stress (reactive oxygen species, malondialdehyde, and glutathione) were measured using ELISA. Western blotting was performed to detect the expression of pyroptosis- and pathway-related proteins. Fibroblast-like synoviocytes of RA (RA-FLS) were treated with TNF-α. Cell migration, invasion, and Caspase-1 levels were assessed through scratch assays, Transwell assays, and flow cytometry, respectively. The correlation between SLC7A11 and immune cell infiltration in RA was analyzed using bioinformatics. Additionally, downstream pathways of SLC7A11 in RA were screened, and the impacts of SLC7A11 on these pathways were validated in vitro.
Results:
CIA mice were successfully established, revealing significant downregulation of SLC7A11 in RA. Staining results indicated that overexpression of SLC7A11 significantly mitigated joint damage in CIA mice. In vitro experiments demonstrated that overexpression of SLC7A11 inhibited migration, invasion, and Caspase-1 expression levels in TNF-α-induced RA-FLSs. Furthermore, SLC7A11 suppressed inflammation, LDH release, and oxidative stress, while inhibiting pyroptosis. SLC7A11 expression was significantly different in multiple immune cells. The IL-17 pathway was identified as a downstream pathway of SLC7A11, and SLC7A11 inhibited the expression of IL-17 pathway proteins. Additionally, rhIL-17A, an activator of the IL-17 pathway, attenuated the inhibitory effects of SLC7A11 on inflammation, oxidative stress, and pyroptosis.
Conclusion:
SLC7A11 suppresses pyroptosis to alleviate RA development by inhibiting the IL-17 pathway.
Insights
Solute carrier family 7 member 11 (SLC7A11) suppresses pyroptosis and inflammation in rheumatoid arthritis (RA) by inhibiting the IL-17 pathway, offering a potential therapeutic target for RA development.
Area of Science:
- Immunology
- Molecular Biology
- Pathology
Background:
- Rheumatoid arthritis (RA) is a complex autoimmune disease with an unclear cause.
- Investigating the role of solute carrier family 7 member 11 (SLC7A11) in RA pathogenesis is crucial for understanding disease mechanisms.
Purpose of the Study:
- To elucidate the mechanisms by which SLC7A11 influences the development of rheumatoid arthritis.
- To explore SLC7A11's potential as a therapeutic target in RA.
Main Methods:
- Utilized collagen-induced arthritis (CIA) mouse models and in vitro RA fibroblast-like synoviocytes (RA-FLS) models.
- Assessed pathological changes, inflammatory markers, oxidative stress, and pyroptosis.
- Analyzed protein expression via Western blotting and immune cell infiltration using bioinformatics.
Main Results:
- Downregulation of SLC7A11 was observed in RA, and its overexpression mitigated joint damage in CIA mice.
- SLC7A11 inhibited RA-FLS migration, invasion, inflammation, oxidative stress, and pyroptosis.
- SLC7A11 was found to suppress the IL-17 pathway, a key driver of RA pathogenesis.
Conclusions:
- SLC7A11 plays a protective role in RA by suppressing pyroptosis and inflammation.
- Inhibition of the IL-17 pathway by SLC7A11 is a critical mechanism in alleviating RA development.
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