Btk inhibition treats TLR7/IFN driven murine lupus

•Btk inhibition reduces autoantibodies, nephritis, and mortality in BXSB-Yaa lupus mice.•Btk inhibition suppresses arthritis development in pristane-induced mouse lupus.•In lupus mice, arthritis can be suppressed without a significant reduction in autoantibodies or IFN.•Btk inhibition can block activation of human macrophages by immune complexes and TLR7.•Btk inhibition can provide therapeutic benefit to SLE patients by affecting both BCR and FcR signaling.

ABSTRACTBruton's tyrosine kinase (Btk) is expressed in a variety of immune cells and previous work has demonstrated that blocking Btk is a promising strategy for treating autoimmune diseases. Herein, we utilized a tool Btk inhibitor, M7583, to determine the therapeutic efficacy of Btk inhibition in two mouse lupus models driven by TLR7 activation and type I interferon. In BXSB-Yaa lupus mice, Btk inhibition reduced autoantibodies, nephritis, and mortality. In the pristane-induced DBA/1 lupus model, Btk inhibition suppressed arthritis, but autoantibodies and the IFN gene signature were not significantly affected; suggesting efficacy was mediated through inhibition of Fc receptors. In vitro studies using primary human macrophages revealed that Btk inhibition can block activation by immune complexes and TLR7 which contributes to tissue damage in SLE. Overall, our results provide translational insight into how Btk inhibition may provide benefit to a variety of SLE patients by affecting both BCR and FcR signaling.