An Apoptotic Caspase Network Safeguards Cell Death Induction in Pyroptotic Macrophages
Pyroptosis has emerged as a key mechanism by which inflammasomes promote host defense against microbial pathogens and sterile inflammation. Gasdermin D (GSDMD)-mediated cell lysis is a hallmark of pyroptosis, but our understanding of cell death signaling during pyroptosis is fragmented. Here, we sho...
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Published in | Cell reports (Cambridge) Vol. 32; no. 4; p. 107959 |
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Main Authors | , , , , , , |
Format | Journal Article |
Language | English |
Published |
United States
Elsevier Inc
28.07.2020
Cell Press Elsevier |
Subjects | |
Online Access | Get full text |
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Summary: | Pyroptosis has emerged as a key mechanism by which inflammasomes promote host defense against microbial pathogens and sterile inflammation. Gasdermin D (GSDMD)-mediated cell lysis is a hallmark of pyroptosis, but our understanding of cell death signaling during pyroptosis is fragmented. Here, we show that independently of GSDMD-mediated plasma membrane permeabilization, inflammasome receptors engage caspase-1 and caspase-8, both of which redundantly promote activation of apoptotic executioner caspase-3 and caspase-7 in pyroptotic macrophages. Impaired GSDMD pore formation downstream of caspase-1 and caspase-8 activation suffices to unmask the apoptotic phenotype of pyroptotic macrophages. Combined inactivation of initiator caspase-1 and caspase-8, or executioner caspase-3 and caspase-7, is required to abolish inflammasome-induced DEVDase activity during pyroptosis and in apoptotic Gsdmd−/− cells. Collectively, these results unveil a robust apoptotic caspase network that is activated in parallel to GSDMD-mediated plasma membrane permeabilization and safeguards cell death induction in pyroptotic macrophages.
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•Wild-type macrophages display caspase-3/7-dependent DEVDase activity during pyroptosis•GSDMD inhibition unmasks an apoptotic cascade downstream of inflammasomes•Inflammasomes trigger apoptosis by distinct mechanisms in GSDMD−/− and Casp1−/− cells•Caspase-1 and caspase-8 activate caspase-3 and caspase-7 to induce apoptosis in GSDMD−/− macrophages
de Vasconcelos et al. demonstrate that an apoptotic cascade is initiated in macrophages undergoing inflammasome-mediated pyroptosis. Caspase-1 and caspase-8 initiate the downstream activation of apoptotic caspase-3 and caspase-7, leading to cleavage of apoptotic markers during pyroptosis. This caspase network explains why inflammasome-activated GSDMD−/− and Casp1−/− cells undergo apoptosis. |
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Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Lead Contact These authors contributed equally |
ISSN: | 2211-1247 2211-1247 |
DOI: | 10.1016/j.celrep.2020.107959 |