Sialoglycans Modulate Siglec-5 – TLR4 Interactions in Osteoarthritis

Summary Osteoarthritis (OA) is characterized by chronic, low-grade inflammation that contributes to cartilage degradation and joint pain. We previously identified Siglec-5/14 in synovial fluid of OA patients (OA SF), which prompted us to investigate its interaction with the sialylated proinflammatory receptor TLR4 in monocytes. Here, we reveal an inverse correlation between Siglec-5 and TLR4, suggesting Siglec-5 may suppress inflammation. To gain mechanistic insights, monocytes stimulated with OA SFs were compared to M-CSF, LPS, and sialidase, to assess patient-specific inflammatory pathways and phenotypes. Notably, OA SF that triggered elevated IL-6 production in monocytes exhibited phenotypes similar to those of LPS- or sialidase-treated cells, reinforcing the role of sialylation patterns influencing OA severity. To confirm direct interaction of Siglec-5 and TLR4, colocalization was analyzed, displaying a time- and sialoglycan-dependent interaction. These findings reveal a Siglec-5-TLR4 axis modulated by sialylation, highlighting a potential strategy for mitigating inflammation and preserve joint integrity in OA. Competing Interest Statement NK authored a patent involving OA diagnostics, and NK hold equity in Lynxon AB. The other authors have declared that no conflict of interest exists. Footnotes Mechanistic insights delineating the involvement of Siglec 5 versus Siglec 14, both with regards to their expression and engagement of intracellular signaling. Both main manuscript and supplementary material are updated.