Jim Middleton
University of Bristol, Bristol, UK
Title: Novel therapeutic approach to inhibit innate immune cell trafficking in inflammation using chemokines and their binding molecules.
Biography
Biography: Jim Middleton
Abstract
Chemokines are involved in driving leukocyte migration into inflamed tissue. They achieve this by being presented to blood leukocytes by heparan sulphate proteoglycans (HSPGs) on the luminal surface of vascular endothelial cells. We have found that in the synovial endothelial cells of rheumatoid arthritis patients there is induction of a CXCL8 binding site on the HSPG syndecan-3. This suggests involvement of syndecan-3 in leukocyte trafficking into the synovium. Indeed we have shown that leukocyte accumulation and cartilage damage is reduced in syndecan-3 null mice with antigen-induced arthritis. Addition of soluble syndecan-3 in vitro binds chemokines CCL2 and CCL7, and redcues chemotactic responses of moncytes to these chemokines. Injection of soluble syndecan-3 reduces leukocyte accumulation and arthritis severity in antigen-induced arthritis. HSPGs interact with basic residues in chemokines. Therefore addition of competing peptides containing these residues should be inhibitory. Indeed we have found some chemokine peptides do inhibit chemokine-HSPG interaction. These peptides bind HS and inhibit chemokine-driven migration of neutrophils across brain microvascular endothelial cells in vitro. Furthermore these chemokine peptides reduce the swelling of joints of mice with antigen-induced arthritis. In conclusion targeting chemokine-HSPG interactions by adding competing soluble HSPGs (syndecans) and chemokine peptides have therapeutic effects and represents a novel therapeutic approach to inhibit innate immune cell trafficking.
