Btk inhibition suppresses agonist-induced human macrophage activation and inflammatory gene expression in RA synovial tissue explants
Bruton’s tyrosine kinase, a downstream target of PI3K signalling, has been shown to be crucial in the B lymphocyte and myeloid cell contribution to murine models of arthritis. Synovial tissue samples were taken from biologically naïve RA (n=16) and PsA (n=12) patients in order to assess the expression of BTK. Separate RA synovial explants (n=8) were used to assess the effects of the specific BTK inhibitor RN486.
BTK was expressed at equivalent levels in both RA and PsA synovial tissue, however expression was limited to B lymphocytes, monocytes, macrophages and mast cells. No relationship between BTK expression levels and patient clinical characteristics were observed. In the presence of RN486 (a BTK inhibitor), IL-6 production in response to Fc receptor and CD40 stimulation was significantly inhibited. This possibly suggests a primary pathway for macrophage activation by BTK. It also significantly inhibited the CD40L-stimulated production of TNF, MMP-1 and MMP-10.
BTK activity is needed for macrophage activation, with the data in this study showing that macrophages would be the most prominent direct targeted cell population by BTK inhibition. Furthermore, BTK also promotes RA synovial tissue cytokine and MMP production. The targeting of BTK may be of therapeutic benefit to the treatment of RA and other inflammatory diseases.