Sialoglycans modulate Siglec-5 - TLR4 Interactions in Osteoarthritis

Osteoarthritis (OA) is characterized by chronic, low-grade inflammation that contributes to cartilage degradation and joint pain. We previously identified Siglecs in the synovial fluid of OA patients (OA-SF), and together with studies implicating Siglecs in arthritic diseases prompted us to investigate the interplay between Siglec-5, Siglec-9, and TLR4 in monocyte regulation during OA. Flow cytometric profiling revealed an inverse correlation between Siglec-5 expression and TLR4 activity, but not Siglec-9, suggesting that Siglec-5 engagement may suppress inflammatory responses. To gain mechanistic insights, we compared monocytes stimulated with OA-SF to those treated with key inflammatory mediators (M-CSF, LPS, and sialidase) to assess patient-specific inflammatory pathways and phenotypes. Further analysis of the TLR4-Siglec crosstalk using the small molecule inhibitor TAK-242 confirmed that sialoglycans modulate TLR4-driven inflammation. Notably, OA-SF from patients with high-grade inflammation led to monocyte expression profiles similar to LPS- or sialidase treated cells, reinforcing the role of sialylation in regulating inflammatory severity in OA. These findings reveal a TLR4-Siglec-5 axis modulated by sialylation, highlighting a potential strategy for mitigating inflammation and preserve joint integrity in OA.