Syndecan-3 is selectively pro-inflammatory in the joint and contributes to antigen-induced arthritis in mice.

Oksana Kehoe,Andrew Eustace,Ofer Reizes,Charlotte Boyes,Jim Middleton,Anwen Williams,Sophie King,Angela Patterson,Neena Kalia

doi:10.1186/ar4610

Abstract

IntroductionSyndecans are heparan sulphate proteoglycans expressed by endothelial cells. Syndecan-3 is expressed by synovial endothelial cells of rheumatoid arthritis (RA) patients where it binds chemokines, suggesting a role in leukocyte trafficking. The objective of the current study was to examine the function of syndecan-3 in joint inflammation by genetic deletion in mice and compare with other tissues.MethodsChemokine C-X-C ligand 1 (CXCL1) was injected in the joints of syndecan-3−/−and wild-type mice and antigen-induced arthritis performed. For comparison chemokine was administered in the skin and cremaster muscle. Intravital microscopy was performed in the cremaster muscle.ResultsAdministration of CXCL1 in knee joints of syndecan-3−/−mice resulted in reduced neutrophil accumulation compared to wild type. This was associated with diminished presence of CXCL1 at the luminal surface of synovial endothelial cells where this chemokine clustered and bound to heparan sulphate. Furthermore, in the arthritis model syndecan-3 deletion led to reduced joint swelling, leukocyte accumulation, cartilage degradation and overall disease severity. Conversely, CXCL1 administration in the skin of syndecan-3 null mice provoked increased neutrophil recruitment and was associated with elevated luminal expression of E-selectin by dermal endothelial cells. Similarly in the cremaster, intravital microscopy showed increased numbers of leukocytes adhering and rolling in venules in syndecan-3−/−mice in response to CXCL1 or tumour necrosis factor alpha.ConclusionsThis study shows a novel role for syndecan-3 in inflammation. In the joint it is selectively pro-inflammatory, functioning in endothelial chemokine presentation and leukocyte recruitment and cartilage damage in an RA model. Conversely, in skin and cremaster it is anti-inflammatory.

Highlights

Syndecans are heparan sulphate proteoglycans expressed by endothelial cells
Sdc-3 deletion reduces neutrophil recruitment in C-X-C ligand 1 (CXCL1)-injected joints To examine the effects of sdc-3 on inflammation we first studied chemokine-driven leukocyte migration into the knee joint
Intra-articular injection of murine CXCL1 stimulated the influx of neutrophils into the synovium of the joints of sdc-3−/−and wild-type mice (Figure 1A), whereas phosphatebuffered saline (PBS)-injected controls were negative for neutrophils

Summary

Introduction

Syndecan-3 is expressed by synovial endothelial cells of rheumatoid arthritis (RA) patients where it binds chemokines, suggesting a role in leukocyte trafficking. Syndecans (sdcs) are heparan sulphate proteoglycans (HSPG) composed of a core protein to which heparan sulphate (HS) glycosaminoglycan chains are covalently attached. These molecules form part of the glycocalyx, which comprises a network of membrane-bound proteoglycans and glycoproteins at the cell surface of endothelial cells [1,2,3]. On endothelial cells they bind and present chemokines to blood leukocytes that leads to leukocyte integrin activation, crawling on the endothelial cell surface and extravasation [12,13,14,15]. Whether sdcs are pro- or antiinflammatory may relate to the particular tissue where they are expressed or the inflammatory state

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