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Inflammasomes Coordinate Pyroptosis and Natural Killer Cell Cytotoxicity to Clear Infection by a Ubiquitous Environmental Bacterium
Open accessAbstract
Defective neutrophils in patients with chronic granulomatous disease (CGD) cause susceptibility to extracellular and intracellular infections. Microbes must first be ejected from intracellular niches to expose them to neutrophil attack, so we hypothesized that inflammasomes detect certain CGD pathogens upstream of neutrophil killing. Here, we identified one such ubiquitous environmental bacterium, Chromobacterium violaceum, whose extreme virulence was fully counteracted by the NLRC4 inflammasome. Caspase-1 protected via two parallel pathways that eliminated intracellular replication niches. Pyroptosis was the primary bacterial clearance mechanism in the spleen, but both pyroptosis and interleukin-18 (IL-18)-driven natural killer (NK) cell responses were required for liver defense. NK cells cleared hepatocyte replication niches via perforin-dependent cytotoxicity, whereas interferon-γ was not required. These insights suggested a therapeutic approach: exogenous IL-18 restored perforin-dependent cytotoxicity during infection by the inflammasome-evasive bacterium Listeria monocytogenes. Therefore, inflammasomes can trigger complementary programmed cell death mechanisms, directing sterilizing immunity against intracellular bacterial pathogens.
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“Nlrc4−/− mice (which are unable to normally activate CASP1) succumb to low amounts of otherwise innocuous environmental opportunists (e.g., Chromobacterium violaceum) [639].”
From Molecular mechanisms of cell death: recommendations of the nomenclature committee on cell death 2018. (2018) · cites this paper as [639]
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Metadata
- Authors
- Maltez, V. I., Tubbs, A. L., Cook, K. D., Aachoui, Y., Falcone, E. L., Holland, S. M., Whitmire, J. K., & Miao, E. A.
- Affiliations
- University of North Carolina at Chapel Hill (US)
- National Institutes of Health (US)
- Corresponding author
- Miao, Edward A.
- ORCID
- Venue
- Immunity
- Publisher
- Elsevier BV
- Published
- 2015-11
- Volume
- 43
- Issue
- 5
- Pages
- 987-997
- ISSN
- 1074-7613 (ISSN-L)
- PMC
- PMC4654968
- OpenAlex
- W2111822935
- Cited by
- 165
- References
- 50
- Citations by year
- 2026: 8 · 2025: 6 · 2024: 13 · 2023: 17 · 2022: 30 · 2021: 11 · 2020: 21 · 2019: 13 · 2018: 21 · 2017: 16 · 2016: 9
- FWCI
- 6.65
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Immunity (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Carolina Digital Repository (University of North Carolina at Chapel Hill) (submittedVersion)
- UNC Libraries
- Funders
- National Institutes of Health (T32 AI7273-27, AI057141)
- National Cancer Institute (P30CA016086)
- National Institute of Allergy and Infectious Diseases (T32AI7273-27, R01AI119073, U54AI057141, AI119073, R01AI074862, AI097518-02S1, R56AI110682, T32AI007273, R01AI097518, AI097518, AI057141)
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill (P30-CA016086)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Inflammasome and immune disorders
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Life Sciences › Immunology and Microbiology › Immunology › Neutrophil, Myeloperoxidase and Oxidative Mechanisms
- Keywords
- inflammasome, NLRC4 inflammasome, pyroptosis, natural killer cells, NK cell cytotoxicity, perforin, Chromobacterium violaceum, chronic granulomatous disease, caspase-1, IL-18, Listeria monocytogenes, intracellular bacterial pathogens, bacterial clearance, liver infection, spleen, sterilizing immunity
- MeSH terms
- Pyroptosis, Animals, Bacterial Infections, Calcium-Binding Proteins, Chromobacterium, Granulomatous Disease, Chronic, Interferon-gamma, Killer Cells, Natural, Listeriosis, Listeria monocytogenes, Liver, Mice, Inbred C57BL, Neutrophils, Spleen, Cell Death, Caspase 1, Interleukin-18, Apoptosis Regulatory Proteins, Mice, Inflammasomes
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