Background: Persistent inflammation contributes to the progression of rheumatoid arthritis (RA); however, the exact molecular mechanisms underlying inflammation in RA are yet to be fully elucidated. Interleukin-25 plays a crucial role in host defense and the pathogenesis of inflammatory diseases. Its specific contribution to RA progression requires further investigation.

Methods: RA-FLSs were treated with tumor necrosis factor-α (TNF-α) to simulate the inflammatory response in the synovium. Furthermore, changes in inflammatory response and bone destruction indicators were assessed after Interleukin-25 (IL-25) intervention. The collagen-induced arthritis (CIA) mouse model was successfully constructed to evaluate the impact of IL-25 on joint inflammation and erosion.

Results: The expression levels of IL-25 were significantly elevated in the synovial tissues of both RA patients and CIA mouse models compared to controls (p < 0.05). In vitro, IL-25 pretreatment substantially suppressed TNF-α-induced upregulation of interleukin-1β (IL-1β), interleukin-6 (IL-6), high mobility group box-1 protein (HMGB1), matrix metalloproteinase-3 (MMP-3), toll-like receptors 4 (TLR4), and NOD-like receptor thermal protein domain-associated protein 3 (NLRP3) in RA-FLSs (p < 0.05, p < 0.01, p < 0.001), and suppressed nuclear factor kappa-B (NF-κB) signaling pathway by reducing p-P65 and p-IκBα protein levels (p < 0.001). In vivo, IL-25 negatively regulated joint inflammation and reduced the degree of bone erosion in mice (p < 0.01, p < 0.0001).

Conclusion: Elevated IL-25 levels exert anti-inflammatory effects both in vitro and in vivo and alleviate RA progression by inhibiting the TLR4/NF-κB/ NLRP3 signaling pathway.