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Pyroptosis and Apoptosis Pathways Engage in Bidirectional Crosstalk in Monocytes and Macrophages.

Cell chemical biology | 2017

Pyroptosis is a lytic form of programmed cell death mediated by the inflammatory caspase-1, -4, and -5. We recently discovered that small-molecule inhibitors of the serine peptidases DPP8 and DPP9 (DPP8/9) induce pro-caspase-1-dependent pyroptosis in monocytes and macrophages. Notably, DPP8/9 inhibitors, unlike microbial agents, absolutely require caspase-1 to induce cell death. Therefore, DPP8/9 inhibitors are useful probes to study caspase-1 in cells. Here, we show that, in the absence of the pyroptosis-mediating substrate gasdermin D (GSDMD), caspase-1 activates caspase-3 and -7 and induces apoptosis, demonstrating that GSDMD is the only caspase-1 substrate that induces pyroptosis. Conversely, we found that, during apoptosis, caspase-3/-7 specifically block pyroptosis by cleaving GSDMD at a distinct site from the inflammatory caspases that inactivates the protein. Overall, this work reveals bidirectional crosstalk between apoptosis and pyroptosis in monocytes and macrophages, further illuminating the complex interplay between cell death pathways in the innate immune system.

Pubmed ID: 28392147 RIS Download

Mesh terms: Amino Acid Sequence | Animals | Apoptosis | Caspase 1 | Caspase 3 | Caspase 7 | Cell Line | Dipeptidyl-Peptidases and Tripeptidyl-Peptidases | HEK293 Cells | Humans | Immunity, Innate | Lipopolysaccharides | Macrophages | Mice | Monocytes | Mutagenesis, Site-Directed | Neoplasm Proteins | Nigericin | Pyroptosis | RAW 264.7 Cells

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