Bruton’s tyrosine kinase (BTK) is indispensable in neutrophils to initiate and maintain skin inflammation in a model of pemphigoid diseases

Summary: Abstract Body: The Tec kinase Bruton’s tyrosine kinase (BTK) is essential for B cell functions rendering it a potential therapeutic taget for antibody-induced autoimmune diseases. The role of BTK in myeloid cells is less understood. More insights into the significance of BTK in myeloid cells is required to evaluate the potential of BTK as therapeutic target in the effector phase of antibody-induced autoimmune diseases when inhibiting the production of autoantibodies usually cannot suppress tissue inflammation swiftly. Such a situation can be found, e.g., in acute flares of pemphigoid diseases, a group of autoimmune diseases. We examined the effect of neutrophil-specific Btk gene knockout and of the BTK inhibitor ibrutinib on skin inflammation in the antibody transfer model of bullous pemphigoid (BP)-like epidermolysis bullosa acquisita (EBA). The model solely reflects the effector phase of antibody-driven autoimmune diseases. Furthermore, we investigated the effect of BTK inhibitors on responses of neutrophils relevant for antibody-induced autoimmune diseases in vitro. Both neutrophil-specific genetic deficiency of BTK and ibrutinib vastly protected from skin inflammation. Stimulation of murine neutrophils with immune complexes activated BTK and induced the release of leukotriene B4 (LTB4) and reactive oxygen species (ROS). Genetic deficiency in BTK nullified LTB4 but not ROS release. In vitro, ibrutinib and other inhibitors of BTK, including rilzabrutinib and CGI-1746, inhibited neutrophil responses to immune complexes. Our results indicate that BTK in neutrophils is essential to initiate and maintain neutrophil recruitment thus precipitating tissue inflammation in EBA. The marked responsiveness of EBA to BTK inhibition results from a nonredundant role of BTK in relaying Fcγ receptor signaling in neutrophils to induce the release of LTB4. This highlights BTK as promising drug target to treat EBA and potentially other antibody-induced autoimmune disease. Henning Olbrich¹, Paul Schilf¹, Sripriya Murthy¹, Sina Gonther¹, Mareike Neumann¹, Christoph Hammers¹, Christian D. Sadik¹ 1. Department of Dermatology, Allergy, and Venereology, Universitat zu Lubeck, Lübeck, SH, Germany. Translational Studies: Preclinical