Caspase-1-induced pyroptosis is an innate immune effector mechanism against intracellular bacteria
Open accessAbstract
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.
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Inflammation and cell death have important regulatory roles in aging, and pyroptosis, as an inflammatory form of cell death, may contribute to the inflammatory response and cellular dysregulation in the aging process.
“Inflammation and cell death have important regulatory roles in aging, and pyroptosis, as an inflammatory form of cell death, may contribute to the inflammatory response and cellular dysregulation in the aging process.243”
From Inflammation and aging: signaling pathways and intervention therapies (2023) · cites this paper as [243]
The Discussion (page unavailable) describes pyroptosis as pro-inflammatory and says it may release inflammatory mediators and cause tissue damage. The paper does not address aging or establish a role for pyroptosis in age-related cellular dysregulation; its findings concern infection and other inflammasome stimuli. (LLM, conf=0.88)
Experimental — accuracy not yet measuredPyroptosis may play a specific role in aging.
“Specifically, pyroptosis may play a specific role in aging.”
From Inflammation and aging: signaling pathways and intervention therapies (2023) · cites this paper as [243]
The Discussion describes pyroptosis in pathogen clearance and possible tissue damage from inflammation, but does not connect it to aging. Searches for aging, age-related processes, and senescence found no passage addressing that connection. (LLM, conf=0.76)
Experimental — accuracy not yet measuredCASP1-driven pyroptosis limits spreading of intracellular bacteria by killing the host cell and generating pore-induced intracellular traps that are disposed of by efferocytosis.
“CASP1-driven pyroptosis limits the spreading of intracellular bacteria by (1) killing the host cell [637], and (2) generating so-called “pore-induced intracellular traps (PITs)”, which essentially are dead macrophages that can be efficiently disposed of (together with the living bacteria they trap) by efferocytosis [638].”
From Molecular mechanisms of cell death: recommendations of the nomenclature committee on cell death 2018. (2018) · cites this paper as [637]
Flagellin can be detected by host PRR TLR5, which triggers pyroptosis of macrophages.
“Strikingly, flagellin can be detected by the host PRR TLR5, which triggers pyroptosis of macrophages ( 75 , 76 ).”
From YdiV regulates Escherichia coli ferric uptake by manipulating the DNA-binding ability of Fur in a SlyD-dependent manner (2020) · cites this paper as [76]
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“Strikingly, flagellin can be detected by the host PRR TLR5, which triggers pyroptosis of macrophages (75,76).”
- Authors
- Miao, E. A., Leaf, I. A., Treuting, P. M., Mao, D. P., Dors, M., Sarkar, A., Warren, S. E., Wewers, M. D., & Aderem, A.
- Affiliations
- Institute for Systems Biology (US)
- University of Washington (US)
- The Ohio State University (US)
- Corresponding author
- Miao, Edward A
- Aderem, Alan
- Venue
- Nature Immunology
- Published
- 2010-11-07
- Volume
- 11
- Issue
- 12
- Pages
- 1136-1142
- ISSN
- 1529-2908 (ISSN-L)
- 1529-2916
- PMC
- PMC3058225
- OpenAlex
- W2097714951
- Cited by
- 1,336
- References
- 53
- Citations by year
- 2026: 44 · 2025: 76 · 2024: 93 · 2023: 99 · 2022: 109 · 2021: 106 · 2020: 99 · 2019: 86 · 2018: 80 · 2017: 78 · 2016: 84 · 2015: 81 · 2014: 69 · 2013: 97 · 2012: 69
- FWCI
- 29.56
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Immunology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Carolina Digital Repository (University of North Carolina at Chapel Hill) (submittedVersion)
- UNC Libraries
- Funders
- National Institute of Allergy and Infectious Diseases (R01AI052286, U54AI057141, AI052286, R01AI025032, K08AI065878)
- 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 › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Keywords
- caspase-1, pyroptosis, innate immunity, intracellular bacteria, NLRC4 inflammasome, Salmonella typhimurium, Legionella pneumophila, Burkholderia thailandensis, macrophages, neutrophils, reactive oxygen species, bacterial clearance, IL-1β, IL-18
- MeSH terms
- Animals, Calcium-Binding Proteins, Cell Separation, Enzyme-Linked Immunosorbent Assay, Flow Cytometry, Immunity, Innate, Immunohistochemistry, Macrophages, Mice, Inbred C57BL, Salmonella Infections, Salmonella typhimurium, Apoptosis, Caspase 1, Apoptosis Regulatory Proteins, Mice, Inflammasomes
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