DPP8 and DPP9 inhibition induces pro-caspase-1-dependent monocyte and macrophage pyroptosis

• DOI: 10.1038/nchembio.2229
• Publication Date: 2016-11-02T09:46:53Z
• Authors: Marian C Okondo; Darren C Johnson; Ramya Sridharan; Eun Bin Go; Ashley J Chui; Mitchell S Wang; Sarah E Poplawski; Wengen Wu; Yuxin Liu; Jack H Lai; David G Sanford; Michael O Arciprete; Todd R Golub; William W Bachovchin; Daniel A Bachovchin
• Keywords: Pyroptosis; Proinflammatory cytokine

Val-boroPro (Talabostat, PT-100), a nonselective inhibitor of post-proline cleaving serine proteases, stimulates mammalian immune systems through an unknown mechanism of action. Despite this lack of mechanistic understanding, Val-boroPro has attracted substantial interest as a potential anticancer agent, reaching phase 3 trials in humans. Here we show that Val-boroPro stimulates the immune system by triggering a proinflammatory form of cell death in monocytes and macrophages known as pyroptosis. We demonstrate that the inhibition of two serine proteases, DPP8 and DPP9, activates the pro-protein form of caspase-1 independent of the inflammasome adaptor ASC. Activated pro-caspase-1 does not efficiently process itself or IL-1β but does cleave and activate gasdermin D to induce pyroptosis. Mice lacking caspase-1 do not show immune stimulation after treatment with Val-boroPro. Our data identify what is to our knowledge the first small molecule that induces pyroptosis and reveals a new checkpoint that controls the activation of the innate immune system.