Dataset Information

Sialoglycans Modulate Siglec-5 – TLR4 Interactions in Osteoarthritis

ABSTRACT: 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.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Cell Culture

SUBMITTER: Johannes Fuchs

LAB HEAD: Alexandra Stubelius

PROVIDER: PXD069055 | Pride | 2025-10-27

REPOSITORIES: Pride

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			Action	DRS
	4149LFQnanoparthumanonlyFusion_210209_210404_210407.xlsx	Xlsx
	Fusion_210209_18.msfView	Msf
	Fusion_210209_18.raw	Raw
	Fusion_210209_21.msfView	Msf
	Fusion_210209_21.raw	Raw

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Project description:Siglec-E is a murine CD33-related siglec that functions as an inhibitory receptor and is expressed mainly on neutrophils and macrophage populations. Recent studies have suggested that siglec-E is an important negative regulator of LPS-TLR4 signalling and one report (Wu et al 2016) claimed that siglec-E is required for TLR4 endocytosis following uptake of Escherichia coli by macrophages and dendritic cells (DCs). Our attempts to reproduce these observations using cells from wildtype (WT) and siglec E deficient mice were unsuccessful. We used a variety of assays to determine if siglec-E expressed by different macrophage populations can regulate TLR-4 signalling in response to LPS, but found no consistent differences in cytokine secretion in vitro and in vivo, comparing 3 different strains of siglec-E-deficient mice with matched WT controls. No evidence was found that the siglec-E deficiency was compensated by expression of siglecs-F and –G, the other murine inhibitory CD33-related siglecs. Quantitative proteomics was used as an unbiased approach and provided additional evidence that siglec-E does not suppress inflammatory TLR4 signaling. Interestingly, proteomics revealed a siglec E dependent alteration in macrophage phenotype that could be relevant to functional responses in host defence. In support of this, siglec-E-deficient mice exhibited enhanced growth of Salmonella enterica serovar Typhimurium in the liver following intravenous infection, but macrophages lacking siglec-E did not show altered uptake or killing of bacteria in vitro. Using various cell types including bone marrow derived DCs (BMDC), splenic DCs and macrophages from WT and siglec-E-deficient mice, we showed that siglec-E is not required for TLR4 endocytosis following E.coli uptake or LPS challenge. We failed to see expression of siglec-E by BMDC even after LPS-induced maturation, but confirmed previous studies that splenic DCs express low levels of siglec-E. Taken together, our findings do not support a major role of siglec-E in regulation of TLR4 signalling functions or TLR4 endocytosis in macrophages or DCs. Instead, they reveal that induction of siglec-E by LPS can modulate the phenotype of macrophages, the functional significance of which is currently unclear.

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Sialoglycans Modulate Siglec-5 – TLR4 Interactions in Osteoarthritis

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