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Pyroptosis triggers pore-induced intracellular traps (PITs) that capture bacteria and lead to their clearance by efferocytosis
Open accessAbstract
Inflammasomes activate caspase-1 in response to cytosolic contamination or perturbation. This inflammatory caspase triggers the opening of the GSDMD pore in the plasma membrane, resulting in lytic cell death called pyroptosis. We had previously assumed that pyroptosis releases intracellular bacteria to the extracellular space. Here, we find that viable bacteria instead remain trapped within the cellular debris of pyroptotic macrophages. This trapping appears to be an inevitable consequence of how osmotic lysis ruptures the plasma membrane, and may also apply to necroptosis and some forms of nonprogrammed necrosis. Although membrane tears release soluble cytosolic contents, they are small enough to retain organelles and bacteria. We call this structure the pore-induced intracellular trap (PIT), which is conceptually parallel to the neutrophil extracellular trap (NET). The PIT coordinates innate immune responses via complement and scavenger receptors to drive recruitment of and efferocytosis by neutrophils. Ultimately, this secondary phagocyte kills the bacteria. Hence, caspase-1–driven pore-induced cell death triggers a multifaceted defense against intracellular bacteria facilitated by trapping the pathogen within the cellular debris. Bona fide intracellular bacterial pathogens, such as Salmonella, must prevent or delay pyroptosis to avoid being trapped in the PIT and subsequently killed by neutrophils.
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“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 [638]
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Metadata
- Authors
- Jorgensen, I., Zhang, Y., Krantz, B. A., & Miao, E. A.
- Affiliations
- Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599 1
- University of North Carolina at Chapel Hill (US)
- University of Maryland, Baltimore (US)
- Corresponding author
- Miao, Edward A.
- Venue
- Journal of Experimental Medicine
- Publisher
- Rockefeller University Press
- Published
- 2016-08-29
- Volume
- 213
- Issue
- 10
- Pages
- 2113-2128
- ISSN
- 0022-1007 (ISSN-L)
- 1540-9538
- PMC
- PMC5030797
- OpenAlex
- W2511127858
- Cited by
- 403
- References
- 43
- Citations by year
- 2026: 21 · 2025: 38 · 2024: 40 · 2023: 57 · 2022: 56 · 2021: 35 · 2020: 46 · 2019: 35 · 2018: 37 · 2017: 32 · 2016: 5
- FWCI
- 18.89
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- The Journal of Experimental Medicine (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-sa)
- PubMed Central (publishedVersion, cc-by-nc-sa)
- PubMed (publishedVersion)
- Carolina Digital Repository (University of North Carolina at Chapel Hill) (submittedVersion)
- UNC Libraries
- Funders
- National Institutes of Health (DK007737, AI097518, AI057141, AI119073, AI077703, 1 S10 OD017984-01A1)
- 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
- pyroptosis, caspase-1, inflammasome, intracellular bacteria, bacterial clearance, efferocytosis, neutrophils, macrophages, osmotic lysis, plasma membrane rupture, necroptosis, neutrophil extracellular traps, complement system, scavenger receptors, Salmonella, innate immunity
- MeSH terms
- Pyroptosis, Animals, Complement System Proteins, Macrophages, Mice, Inbred C57BL, Necrosis, Neutrophils, Phagocytosis, Salmonella typhimurium, Solubility, Intracellular Space, Green Fluorescent Proteins, Microbial Viability, Receptors, Scavenger, Mice
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