A novel Highly Specific Small Molecule Inhibitor for BTK Suppresses Fc Receptor Function in Macrophages and Prevents Inflammatory Arthritis (96.18)

• Published in: The Journal of immunology (1950) 2010-04, Vol.184 (1_Supplement), p.96-96.18
• Main Authors: Reif, Karin, Huang, Tao, Barbosa, Jim, Hymowitz, Sarah, Gallion, Steven, Hurez, Vincent, Maciejewski, Patricia, Dennis Jr, Glynn, Rong, Hong, Shen, Fang, Diehl, Lauri, DeFroge, Laura, Lee, Wyne, Balazs, Mercedesz, Currie, Kevin, DiPaolo, Julie
• Format: Article
• Language: English
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.184.Supp.96.18

Activating Fc receptors and inflammatory cytokine production by macrophages have been implicated in the development and pathology of arthritis. However, the molecular components that mediate these events are not well characterized. Here we identify Bruton’s tyrosine kinase (BTK) as an essential player not only in B-cell dependent but also in myeloid-cell dependent inflammatory arthritis using a novel highly specific small molecule inhibitor of BTK (BTK SMI). In rodent models of collagen-induced arthritis, treatment with BTK SMI inhibits disease by at least two mechanisms: preventing autoantibody production and suppressing inflammatory cytokine production. Specifically, BTK SMI treatment prevents signaling and inflammatory cytokine production in response to immune complex activation in macrophages. Pathways found in rodents translate to human as BTK SMI prevents Fc receptor induced cytokine production in human monocytes. These data indicate that BTK SMI may be beneficial for the treatment of arthritis and that BTK contributes substantially to myeloid cell-dependent disease pathogenesis.