An Apoptotic Caspase Network Safeguards Cell Death Induction in Pyroptotic Macrophages

• Published in: Cell reports (Cambridge) 2020-07, Vol.32 (4), p.107959-107959, Article 107959
• Main Authors: de Vasconcelos, Nathalia Moraes, Van Opdenbosch, Nina, Van Gorp, Hanne, Martín-Pérez, Rosa, Zecchin, Annalisa, Vandenabeele, Peter, Lamkanfi, Mohamed
• Format: Article
• Language: English
• Subjects: Animals; apoptosis; Apoptosis - physiology; Apoptosis Regulatory Proteins - metabolism; Caspase 1 - metabolism; Caspase 1 - physiology; Caspase 3 - metabolism; Caspase 7 - metabolism; Caspase 8 - metabolism; Caspase 8 - physiology; caspase-1; caspase-3; caspase-7; caspase-8; Caspases - metabolism; Cell Death; Cell Membrane - metabolism; Female; GSDMD; inflammasome; Inflammasomes - metabolism; Intracellular Signaling Peptides and Proteins - metabolism; Macrophages - metabolism; Male; Mice; Mice, Inbred C57BL; Phosphate-Binding Proteins - metabolism; pyroptosis; Pyroptosis - physiology
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2020.107959

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. [Display omitted] •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.