Regulation of fibroblast response to IL-1 in rheumatoid arthritis by the transmembrane heparane sulfate proteoglycan syndecan-4

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Fibroblast-like synoviocytes from patients with rheumatoid arthritis (RA-FLS) exhibit a stable activation that is associated with the imprinting of important pathogenic features including an altered response to extracellular signals. In the last funding period, we could show that the transmembrane heparan sulfate proteogylcan syndecan-4 (sdc4) not only is involved in the attachment of RA-FLS to cartilage, but also regulates the responsiveness of these cells to interleukin-1 (IL-1). We could demonstrate that IL-1 directly binds to sdc4 and leads to its dimerization, which is independent of the IL-1 receptor 1(IL-1R1). Strikingly, IL-1 induced dimerization of sdc4 regulates caveolin vesicle-mediated trafficking of the IL-1R. The loss of sdc4 or the inhibition of its dimerization by specific antibodies largely abolishes the surface presentation IL-1R1 on FLS in vitro and in vivo and reduces the severity of chronic destructive arthritis in mice. Based on these data, we now want to use recently generated mutants of sdc4 along with protein biochemical approaches and life cell imaging techniques to study the detailed mechanisms by which sdc4 controls IL-1R1 trafficking. In addition, we will analyse the in vivo relevance of our findings in our established animal models of RA. These data will provide new insights into inflammatory tissue remodelling in RA and contribute to the further development of our anti-sdc4 antibody strategy for the treatment of RA.