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Updated: May 1, 2026
Evaluation of Caspase Activation to Assess Innate Immune Cell Death
Published on: January 20, 2023
Caspase-11 activation requires lysis of pathogen-containing vacuoles by IFN-induced GTPases
Etienne Meunier1, Mathias S Dick2, Roland F Dreier2
1Focal Area Infection Biology, Biozentrum, University of Basel, CH-4056 Basel, Switzerland.
Abstract:
Lipopolysaccharide from Gram-negative bacteria is sensed in the host cell cytoplasm by a non-canonical inflammasome pathway that ultimately results in caspase-11 activation and cell death. In mouse macrophages, activation of this pathway requires the production of type-I interferons, indicating that interferon-induced genes have a critical role in initiating this pathway. Here we report that a cluster of small interferon-inducible GTPases, the so-called guanylate-binding proteins, is required for the full activity of the non-canonical caspase-11 inflammasome during infections with vacuolar Gram-negative bacteria. We show that guanylate-binding proteins are recruited to intracellular bacterial pathogens and are necessary to induce the lysis of the pathogen-containing vacuole. Lysis of the vacuole releases bacteria into the cytosol, thus allowing the detection of their lipopolysaccharide by a yet unknown lipopolysaccharide sensor. Moreover, recognition of the lysed vacuole by the danger sensor galectin-8 initiates the uptake of bacteria into autophagosomes, which results in a reduction of caspase-11 activation. These results indicate that host-mediated lysis of pathogen-containing vacuoles is an essential immune function and is necessary for efficient recognition of pathogens by inflammasome complexes in the cytosol.
Insights
Guanylate-binding proteins are essential for the non-canonical inflammasome pathway, which detects Gram-negative bacteria. These proteins trigger vacuole lysis, enabling bacterial lipopolysaccharide detection and subsequent caspase-11 activation.
Area of Science:
- Immunology
- Cell Biology
- Microbiology
Background:
- Gram-negative bacteria lipopolysaccharide (LPS) triggers host cell death via a non-canonical inflammasome pathway involving caspase-11.
- Type-I interferons and interferon-induced genes are critical for initiating this pathway in mouse macrophages.
Purpose of the Study:
- To investigate the role of interferon-inducible genes in the non-canonical caspase-11 inflammasome pathway.
- To identify specific host factors required for sensing intracellular Gram-negative bacteria.
Main Methods:
- Investigated the function of guanylate-binding proteins (GBPs) in the caspase-11 inflammasome pathway.
- Utilized mouse macrophages infected with vacuolar Gram-negative bacteria.
- Assessed bacterial vacuole lysis, bacterial release into the cytosol, and inflammasome activation.
Main Results:
- A cluster of guanylate-binding proteins (GBPs) is required for full non-canonical caspase-11 inflammasome activity.
- GBPs are recruited to intracellular bacteria and induce lysis of the pathogen-containing vacuole.
- Vacuole lysis releases bacteria, allowing LPS detection and inflammasome activation; however, galectin-8 mediated autophagosome uptake reduces caspase-11 activation.
Conclusions:
- Host-mediated lysis of pathogen-containing vacuoles is a crucial immune function.
- Efficient cytosolic recognition of pathogens by inflammasomes necessitates vacuole lysis.
- GBPs play a key role in initiating the host immune response to intracellular Gram-negative bacteria.
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