| Summary: | <p>Inflammation driven by dysregulated NF-κB signaling is a defining feature of many human diseases. Significant side-effect profiles of current anti-inflammatory medicines create an unmet need for new anti-inflammatory drugs. Drug repurposing, the use of approved medicines for novel indications, is an attractive alternative to <em>de novo</em> drug development. Here, I aimed to identify FDA-approved medicines that inhibit NF-κB activation and reduce inflammation. Using NF-κB reporter cell lines, I identified regorafenib and sorafenib as NF-κB inhibitors in macrophages. Both drugs effectively reduced pro-inflammatory mediator production in primary murine and human macrophages and inhibited monosodium urate (MSU) crystal-induced NF-κB-mediated NLRP3 inflammasome priming in murine bone marrow-derived macrophages (BMDMs). In MSU crystal-induced peritonitis, a model of acute inflammation, prophylactic administration with regorafenib reduced peritoneal neutrophil influx and pro-inflammatory cytokine and chemokine production compared to vehicle at 4 h and inhibited neutrophil and monocyte recruitment at 16 h post-MSU crystal injection. Importantly, similar anti-inflammatory effects were observed after therapeutic intraperitoneal regorafenib administration. Mechanistically, regorafenib reduced inflammation <em>in vivo</em> by attenuating NF-κB-dependent NLRP3 inflammasome priming, reducing peritoneal IL-1β and ASC levels and suppressing pro-Caspase-1 production in peritoneal exudate cells. It further inhibited NF-κB-mediated MSU crystal-induced CCL2 chemokine production and retained monocytes in their splenic reservoir. In addition, regorafenib reduced circulating neutrophil numbers <em>in vivo</em> and inhibited transendothelial neutrophil migration <em>in vitro</em>.</p>
<p>The findings of this thesis demonstrate that a macrophage-based drug repurposing strategy can be employed to identify FDA-approved medicines with previously unreported NF-κB inhibitory and anti-inflammatory properties <em>in vitro</em> and <em>in vivo</em>.</p>
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