Regulation of soluble CD93 and its function in inflammation

Abstract

CD93 is known to be involved in the regulation of phagocytosis and cell adhesion. CD93 is typically membrane-bound, but a soluble form was recently reported. Currently, the role of soluble CD93 in monocytes function remains unknown. In the present study, the regulation of CD93 expression and soluble CD93 production were examined. The functional effect of soluble CD93 was also studied on THP-1 monocytic cells and human primary monocytes. The results showed that inflammatory stimuli, LPS and TNFα, increased CD93 surface expression and also the production of soluble CD93 from human monocytes. The inflammatory induction of soluble CD93 production was confirmed in mice injected intraperitoneally with thioglycollate or LPS. To clarify the functional role of soluble CD93, anti-CD93 monoclonal antibodies were developed by phage-display method from na??ve human antibody library. A recombinant form of human soluble CD93 was also prepared and verified its effect on human primary monocytes and a monocytic cell line. Soluble CD93 activated cell adhesion and phagocytic activities. Notably, soluble CD93 also increased monocyte sensitivity to subsequent TLR stimulation, e.g., by LPS; this was evidenced by increases in differentiation marker expression and pro-inflammatory cytokine production. To investigate the role of soluble CD93 in the pathogenensis of chronic inflammatory diseases, CD93 expression and the amounts of soluble CD93 were examined in synovial tissues and fluids of patients with rheumatoid arthritis. CD93 expression was up-regulated in synovial tissues and soluble CD93 was increased in synovial fluid in rheumatoid arthritis, but not osteoarthritis. These data revealed a novel function for soluble CD93 that may have implications in inflammation and inflammatory diseases such as rheumatoid arthritis.