Abstract
BackgroundSyndecans are heparan sulfate proteoglycans that occur in membrane-bound or soluble forms. Syndecan-3, the least well-characterised of the syndecan family, is highly expressed on synovial endothelial cells in rheumatoid arthritis patients. Here, it binds pro-inflammatory chemokines with evidence for a role in chemokine presentation and leukocyte trafficking into the joint, promoting the inflammatory response. In this study, we explored the role of soluble syndecan-3 as a binder of chemokines and as an anti-inflammatory and therapeutic molecule.MethodsA human monocytic cell line and CD14+ PBMCs were utilised in both Boyden chamber and trans-endothelial migration assays. Soluble syndecan-3 was tested in antigen-induced and collagen-induced in vivo arthritis models in mice. ELISA and isothermal fluorescence titration assays assessed the binding affinities. Syndecan-3 expression was identified by flow cytometry and PCR, and levels of shedding by ELISA.ResultsUsing in vitro and in vivo models, soluble syndecan-3 inhibited leukocyte migration in vitro in response to CCL7 and its administration in murine models of rheumatoid arthritis reduced histological disease severity. Using isothermal fluorescence titration, the binding affinity of soluble syndecan-3 to inflammatory chemokines CCL2, CCL7 and CXCL8 was determined, revealing little difference, with Kds in the low nM range. TNFα increased cell surface expression and shedding of syndecan-3 from cultured human endothelial cells. Furthermore, soluble syndecan-3 occurred naturally in the sera of patients with rheumatoid arthritis and periodontitis, and its levels correlated with syndecan-1.ConclusionsThis study shows that the addition of soluble syndecan-3 may represent an alternative therapeutic approach in inflammatory disease.
Highlights
Syndecans are heparan sulfate proteoglycans that occur in membrane-bound or soluble forms
It is proposed that shedding can serve a range of functions including the removal of cells from points of focal adhesion to the extracellular matrix, removing ligands associated with endothelial heparan sulfate (HS) which could create paracrine effectors, or to release soluble syndecans that can compete for ligands with their membrane-bound counterparts [17,18,19,20]
Chemokines bind to soluble syndecan-3, comparison with HS In an attempt to further the work carried out by Patterson et al on syndecan-3 chemokine binding on endothelial cell (EC) in the rheumatoid arthritis (RA) synovium [28, 29], we tested the binding affinities of clinically relevant chemokines to commercially sourced soluble syndecan-3 using Isothermal fluorescence titration (IFT)
Summary
Syndecans are heparan sulfate proteoglycans that occur in membrane-bound or soluble forms. Syndecan-3, the least well-characterised of the syndecan family, is highly expressed on synovial endothelial cells in rheumatoid arthritis patients It binds pro-inflammatory chemokines with evidence for a role in chemokine presentation and leukocyte trafficking into the joint, promoting the inflammatory response. While the true function of shedding may not yet fully be understood, increases in serum concentrations of syndecan-1 have been detected in chronic kidney disease [21], inflammatory bowel disease [22], systemic lupus erythematosus [23] and periodontitis [24] As these diseases all involve damage to endothelial surfaces, an increase in the serum levels could represent and correlate with a disruption or destruction of the glycocalyx. This figure highlights the complexity of RA and a gap in our understanding of the disease and the mechanism required to develop more effective treatments
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