Knockdown of Galectin-9 a potential therapeutic strategy for rheumatoid arthritis

A recent study featured in Biochemical Pharmacology has revealed that the silencing of Gal-9 resulted in a significant reduction in the proliferation, migration, invasion, and expression of cytokines and matrix metalloproteinases (MMPs). Furthermore, this silencing induced apoptosis in tumor necrosis factor (TNF-α) induced RA-fibroblast-like synoviocytes (FLSs), primarily through the modulation of the musculoaponeurotic fibrosarcoma oncogene homolog (MAFB) and the phosphoinositide 3-kinase (PI3K)/alpha serine/threonine-protein kinase (AKT) pathway.

Jia and colleagues conducted the comprehensive study examining Gal-9 expression in clinical samples, specifically synovial tissue obtained from knee arthroplasty in patients diagnosed with rheumatoid arthritis (RA) and osteoarthritis (OA). Elevated Gal-9 levels were identified in RA synovium compared to OA patients. Additionally, after treatment with a tumor necrosis factor-alpha (TNF-α) inhibitor, a significant decrease in Gal-9 was observed in the plasma of RA patients. Transcriptome sequencing provided insights into Gal-9’s involvement in modulating the TNF-α pathway.

Further experiments demonstrated that TNF-α stimulation led to increased Gal-9 expression in FLSs. Silencing Gal-9 substantially suppressed TNF-α-induced proliferation, migration, and inflammatory responses. The study highlighted Gal-9’s interaction with MAFB, affecting the PI3K/AKT/ mammalian target of rapamycin (mTOR) pathway, as a key mechanism behind these effects. when Gal-9 was knocked down in the CIA model, it exhibited the potential to mitigate arthritis progression.

Gal-9 is a key factor in immune regulation across tumors, viral infections, and autoimmune conditions. its interaction with Tim-3 is critical in tumor immunity, and inhibiting the Gal-9/Tim-3 pathway shows potential in stimulating anti-tumor immune responses and impeding tumor growth.

In another study involving 105 RA patients, Wang et al. observed higher Gal-9 levels in the RA group compared to healthy controls. Plasma Gal-9 levels were found to directly correlate with Gal-9 expression in total lymphocytes and CD3+ T cells, as well as with C-reactive protein (CRP), Simplified Disease Activity Index (SDAI), and Clinical Disease Activity Index (CDAI) markers in RA patients. Furthermore, Gal-9 expressions in various T cell subsets, such as CD4+, CD8+, Treg, and double negative T (DNT) cells, exhibited positive correlations with plasma TNF-α and vascular endothelial growth factor (VEGF) levels in RA patients. The findings suggest that Gal-9 holds promise as a potential biomarker for assessing RA disease activity. Additionally, its association with angiogenesis in RA warrants further investigation,

The present study’s findings underscore the significant effect of Gal-9 knockdown on multiple facets of TNF-α-induced RA-FLSs. The observed inhibition of proliferation, migration, invasion, reduced cytokine and MMP expression, coupled with the promotion of apoptosis, points to Gal-9 as a promising therapeutic target. Through its modulation of the MAFB and PI3K/AKT pathway, Gal-9 exhibits potential avenues for therapeutic intervention in the management of RA.

References

1. Jia Q, Che Q, Zhang X, Chen J, Ren C, Wu Y, et al. Knockdown of Galectin-9 alleviates rheumatoid arthritis through suppressing TNF-α-induced activation of fibroblast-like synoviocytes. Biochem Pharmacol. 2023 Dec 21;115994.

2. Wang Y, Song L, Sun J, Sui Y, Li D, Li G, et al. Expression of Galectin-9 and correlation with disease activity and             vascular endothelial growth factor in rheumatoid arthritis. Clin Exp Rheumatol. 2020;38(4):654–61.

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