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Updated: Jun 6, 2026
Evaluation of Caspase Activation to Assess Innate Immune Cell Death
Published on: January 20, 2023
Caspase-1-induced pyroptosis is an innate immune effector mechanism against intracellular bacteria
Edward A Miao1, Irina A Leaf, Piper M Treuting
1Institute for Systems Biology, Seattle, Washington, USA. emiao@systemsbiology.org
Abstract:
Macrophages mediate crucial innate immune responses via caspase-1-dependent processing and secretion of interleukin 1β (IL-1β) and IL-18. Although infection with wild-type Salmonella typhimurium is lethal to mice, we show here that a strain that persistently expresses flagellin was cleared by the cytosolic flagellin-detection pathway through the activation of caspase-1 by the NLRC4 inflammasome; however, this clearance was independent of IL-1β and IL-18. Instead, caspase-1-induced pyroptotic cell death released bacteria from macrophages and exposed the bacteria to uptake and killing by reactive oxygen species in neutrophils. Similarly, activation of caspase-1 cleared unmanipulated Legionella pneumophila and Burkholderia thailandensis by cytokine-independent mechanisms. This demonstrates that activation of caspase-1 clears intracellular bacteria in vivo independently of IL-1β and IL-18 and establishes pyroptosis as an efficient mechanism of bacterial clearance by the innate immune system.
Insights
Caspase-1 activation clears intracellular bacteria through pyroptosis, a cell death mechanism. This innate immune response is independent of IL-1β and IL-18, revealing a novel bacterial clearance pathway.
Area of Science:
- Immunology
- Microbiology
- Cell Biology
Background:
- Macrophages utilize caspase-1 for processing and secreting IL-1β and IL-18, key cytokines in innate immunity.
- Wild-type Salmonella typhimurium infection is typically lethal in mice.
- The NLRC4 inflammasome senses cytosolic flagellin, activating caspase-1.
Purpose of the Study:
- To investigate the role of caspase-1 activation in bacterial clearance, independent of IL-1β and IL-18.
- To elucidate the mechanism by which caspase-1 activation leads to bacterial clearance.
- To determine if pyroptosis is an effective in vivo mechanism for clearing intracellular bacteria.
Main Methods:
- Infection of mice with flagellin-expressing Salmonella typhimurium.
- Analysis of bacterial clearance pathways, including caspase-1 activation and inflammasome signaling.
- Assessment of cytokine-independent mechanisms and pyroptotic cell death.
- Testing clearance of Legionella pneumophila and Burkholderia thailandensis.
Main Results:
- A flagellin-expressing Salmonella strain was cleared via NLRC4 inflammasome activation of caspase-1, independent of IL-1β and IL-18.
- Caspase-1-induced pyroptosis released bacteria from macrophages, facilitating neutrophil-mediated killing by reactive oxygen species.
- Caspase-1 activation also cleared Legionella pneumophila and Burkholderia thailandensis through cytokine-independent pathways.
- Pyroptosis was identified as an efficient mechanism for in vivo bacterial clearance.
Conclusions:
- Caspase-1 activation clears intracellular bacteria in vivo independently of IL-1β and IL-18.
- Pyroptosis is an effective innate immune mechanism for bacterial clearance.
- This study reveals a novel cytokine-independent pathway for combating bacterial infections.
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