An Apoptotic Caspase Network Safeguards Cell Death Induction in Pyroptotic Macrophages
Nathalia Moraes de Vasconcelos,
Nina Van Opdenbosch,
Hanne Van Gorp,
Rosa Martín-Pérez,
Annalisa Zecchin,
Peter Vandenabeele,
Mohamed Lamkanfi
Affiliations
Nathalia Moraes de Vasconcelos
Department of Internal Medicine and Pediatrics, Ghent University, 9052 Ghent, Belgium; VIB Center for Inflammation Research, 9052 Ghent, Belgium
Nina Van Opdenbosch
Department of Internal Medicine and Pediatrics, Ghent University, 9052 Ghent, Belgium; VIB Center for Inflammation Research, 9052 Ghent, Belgium; Janssen Immunosciences, World Without Disease Accelerator, Pharmaceutical Companies of Johnson & Johnson, Beerse 2340, Belgium
Hanne Van Gorp
Department of Internal Medicine and Pediatrics, Ghent University, 9052 Ghent, Belgium; VIB Center for Inflammation Research, 9052 Ghent, Belgium
Rosa Martín-Pérez
Janssen Immunosciences, World Without Disease Accelerator, Pharmaceutical Companies of Johnson & Johnson, Beerse 2340, Belgium
Annalisa Zecchin
Janssen Immunosciences, World Without Disease Accelerator, Pharmaceutical Companies of Johnson & Johnson, Beerse 2340, Belgium
Peter Vandenabeele
VIB Center for Inflammation Research, 9052 Ghent, Belgium; Department of Biomedical Molecular Biology, Ghent University, Ghent 9052, Belgium; Methusalem program, Ghent University, Ghent 9052, Belgium
Mohamed Lamkanfi
Department of Internal Medicine and Pediatrics, Ghent University, 9052 Ghent, Belgium; VIB Center for Inflammation Research, 9052 Ghent, Belgium; Janssen Immunosciences, World Without Disease Accelerator, Pharmaceutical Companies of Johnson & Johnson, Beerse 2340, Belgium; Corresponding author
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.
