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Updated: Oct 16, 2025
Detection of Inflammasome Activation and Pyroptotic Cell Death in Murine Bone Marrow-derived Macrophages
Published on: May 21, 2018
NLRC4 inflammasome-dependent cell death occurs by a complementary series of three death pathways and determines
Peipei Zhang1, Yifei Liu2, Lichen Hu2
1State Key Laboratory of Cellular Stress Biology, Xiang'an Hospital of Xiamen University, Cancer Research Center of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian 361102, China.
Abstract:
Inflammasome is an innate immune defense mechanism, but its overactivation can lead to host death. Here, we show that cell death dictates mouse death caused by NLRC4 inflammasome overactivation. To execute NLRC4-dependent cell death, three death pathways complement each other in a specific order: Pyroptosis pathway requiring caspase-1 and GSDMD is the default path; impairment of it initiates ASC-mediated caspase-8–dependent apoptosis; when these two pathways are blocked, caspase-1 triggers intrinsic apoptotic pathway. Blocking one or two of these death pathways inhibits induction of various cytokines and lipid mediators, but mice still succumb, and only genetic deletions that block all death paths prevent NLRC4-mediated cell death, tissue damage, and mice death. In addition, infection of nonpropagative Salmonella-caused mice death is attenuated by blocking these death pathways. Thus, to reduce the lethality of infection-related diseases, preventing cell death might be necessary when propagation of infected pathogen was controlled by other means.
Insights
Overactivated inflammasomes cause host death via pyroptosis, apoptosis, and intrinsic pathways. Blocking all three cell death routes prevents death from NLRC4 inflammasome overactivation and Salmonella infection.
Area of Science:
- Immunology
- Cell Biology
- Pathology
Background:
- The inflammasome is a critical innate immune sensor.
- Overactivation of inflammasomes, such as NLRC4, can lead to detrimental host responses and death.
- Understanding the mechanisms of inflammasome-induced cell death is crucial for treating inflammatory diseases.
Purpose of the Study:
- To investigate the cell death pathways involved in NLRC4 inflammasome-mediated lethality.
- To determine if blocking these cell death pathways can prevent host death during inflammasome overactivation and infection.
Main Methods:
- Genetic deletion of key components in inflammasome-induced cell death pathways (pyroptosis, apoptosis).
- Assessment of cell death, cytokine induction, tissue damage, and survival in mouse models.
- Infection models using nonpropagative Salmonella.
Main Results:
- NLRC4 inflammasome overactivation triggers host death through a sequential interplay of pyroptosis (caspase-1/GSDMD), ASC-mediated apoptosis (caspase-8), and intrinsic apoptosis (caspase-1).
- Blocking one or two pathways reduced cytokine induction but did not prevent host death.
- Complete blockade of all three cell death pathways prevented NLRC4-induced cell death, tissue damage, and mortality.
- Blocking these death pathways attenuated mortality in mice infected with nonpropagative Salmonella.
Conclusions:
- Cell death is the critical determinant of host mortality during NLRC4 inflammasome overactivation.
- Targeting multiple cell death pathways simultaneously offers a potential therapeutic strategy to mitigate lethal inflammatory responses and certain infections.
- Preventing cell death may be a viable approach for reducing lethality in infections where pathogen replication is controlled by other means.
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