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Publication - Dr Angela Nobbs

    Soluble syndecan-3 is a chemokine trap reducing leukocyte migration and disease severity in models of rheumatoid arthritis

    Citation

    Eustace, A, McNaughton, E, King, S, Kehoe, O, Kungl, A, Mattey, DL, Nobbs, A, Williams, N & Middleton, J, 2019, ‘Soluble syndecan-3 is a chemokine trap reducing leukocyte migration and disease severity in models of rheumatoid arthritis’. Arthritis Research and Therapy.

    Abstract

    Syndecans are heparan sulphate 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 and promoting the inflammatory response. Using in vitro and in vivo models we explore a novel therapeutic approach of administering soluble syndecan-3 to bind and compete for presented chemokines, thus acting as a chemokine trap. Soluble syndecan-3 inhibited leukocyte migration in vitro in response to CCL7 and its administration in models of rheumatoid arthritis reduced histological disease severity. Using isothermal fluoresence titration the binding affinity of soluble syndecan-3 to inflammatory chemokines CCL2, CCL7 41 and CXCL8 was determined, revealing subtle variations, with Kds in the low to mid nM range. TNFα increased cell surface expression and shedding of syndecan-3 from cultured 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. This study shows that addition of soluble syndecan-3 may represent an alternative therapeutic approach in inflammatory disease.

    Full details in the University publications repository