Selective spleen tyrosine kinase inhibition delays autoimmune arthritis in mice

Spleen tyrosine kinase (SYK) has an important role in immunoreceptor signaling, and SYK inhibition has accordingly attenuated immune-mediated injury in several models. Therefore, the present study examined the effect of SYK inhibition with the selective spleen tyrosine kinase inhibitor P505-15 in experimental rheumatoid arthritis (RA) using a murine model of collagen-induced arthritis (CIA). Treatment with the selective SYK inhibitor P505-15, a small molecule kinase inhibitor selective for SYK, led to a reduction in arthritis score and attenuated histological damage. P505-15 reduced cartilage destruction and macrophage infiltration in CIA mice. In addition, P505-15-treated mice showed lower circulating levels of type II-collagen immunoglobulin (Ig)G1 and IgG2 and pro-inflammatory cytokines. Importantly, P505-15 treatment markedly reduced the interleukin 1 beta-stimulated inflammatory response in human RA synovial cells. Given these encouraging results, a key function for SYK in the development of RA was identified, highlighting that SYK may be a potential therapeutic target for human RA.