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Updated: Dec 13, 2025
Author Spotlight: THP-1 Macrophage Response to LPS/ATP — Unveiling the Pyroptosis, Apoptosis, and Necroptosis Spectrum
Published on: May 3, 2024
An Apoptotic Caspase Network Safeguards Cell Death Induction in Pyroptotic Macrophages
Nathalia Moraes de Vasconcelos1, Nina Van Opdenbosch2, Hanne Van Gorp1
1Department of Internal Medicine and Pediatrics, Ghent University, 9052 Ghent, Belgium; VIB Center for Inflammation Research, 9052 Ghent, Belgium.
Abstract:
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.
Insights
Pyroptosis involves inflammasomes and Gasdermin D (GSDMD) cell lysis. This study reveals a parallel apoptotic caspase network activating alongside GSDMD, ensuring cell death during pyroptosis.
Area of Science:
- Immunology
- Cell Biology
- Molecular Biology
Background:
- Pyroptosis is a critical inflammasome-mediated cell death pathway crucial for host defense against pathogens and sterile inflammation.
- Gasdermin D (GSDMD)-dependent plasma membrane permeabilization is a defining feature of pyroptosis, but the complete cell death signaling cascade remains incompletely understood.
Purpose of the Study:
- To elucidate the cell death signaling pathways activated during pyroptosis, independent of GSDMD-mediated membrane permeabilization.
- To investigate the role of caspases in pyroptotic cell death signaling.
Main Methods:
- Utilized pyroptotic macrophages as a model system.
- Investigated inflammasome receptor engagement with caspase-1 and caspase-8.
- Assessed the activation of executioner caspases (caspase-3 and caspase-7) and DEVDase activity.
- Examined cells with impaired GSDMD pore formation (Gsdmd-/-).
Main Results:
- Inflammasome receptors activate caspase-1 and caspase-8 independently of GSDMD-mediated plasma membrane permeabilization.
- Caspase-1 and caspase-8 redundantly activate apoptotic executioner caspases (caspase-3 and caspase-7) in pyroptotic macrophages.
- Inactivation of both initiator caspases (caspase-1 and caspase-8) or executioner caspases (caspase-3 and caspase-7) is necessary to abolish inflammasome-induced DEVDase activity.
Conclusions:
- A robust apoptotic caspase network operates in parallel to GSDMD-mediated lysis during pyroptosis.
- This parallel caspase activation pathway safeguards efficient cell death induction in pyroptotic macrophages, even with impaired GSDMD function.
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