Caspase-11 increases susceptibility to Salmonella infection in the absence of caspase-1
Open accessAbstract
Inflammasomes are cytosolic multiprotein complexes assembled by intracellular nucleotide-binding oligomerization domain (NOD)-like receptors (NLRs) and they initiate innate immune responses to invading pathogens and danger signals by activating caspase-1 (ref. 1). Caspase-1 activation leads to the maturation and release of the pro-inflammatory cytokines interleukin (IL)-1β and IL-18, as well as lytic inflammatory cell death known as pyroptosis. Recently, a new non-canonical inflammasome was described that activates caspase-11, a pro-inflammatory caspase required for lipopolysaccharide-induced lethality. This study also highlighted that previously generated caspase-1 knockout mice lack a functional allele of Casp11 (also known as Casp4), making them functionally Casp1 Casp11 double knockouts. Previous studies have shown that these mice are more susceptible to infections with microbial pathogens, including the bacterial pathogen Salmonella enterica serovar Typhimurium (S. typhimurium), but the individual contributions of caspase-1 and caspase-11 to this phenotype are not known. Here we show that non-canonical caspase-11 activation contributes to macrophage death during S. typhimurium infection. Toll-like receptor 4 (TLR4)-dependent and TIR-domain-containing adaptor-inducing interferon-β (TRIF)-dependent interferon-β production is crucial for caspase-11 activation in macrophages, but is only partially required for pro-caspase-11 expression, consistent with the existence of an interferon-inducible activator of caspase-11. Furthermore, Casp1(-/-) mice were significantly more susceptible to infection with S. typhimurium than mice lacking both pro-inflammatory caspases (Casp1(-/-) Casp11(-/-)). This phenotype was accompanied by higher bacterial counts, the formation of extracellular bacterial microcolonies in the infected tissue and a defect in neutrophil-mediated clearance. These results indicate that caspase-11-dependent cell death is detrimental to the host in the absence of caspase-1-mediated innate immunity, resulting in extracellular replication of a facultative intracellular bacterial pathogen.
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Type I IFN and IFNG contribute to pyroptosis by promoting transactivation of CASP11 through an IFNAR1-dependent or IFNGR1-dependent mechanism initiated by TLR4 or IL18 signaling.
“type I IFN and IFN gamma (IFNG) also contribute to pyroptosis by promoting: (1) the transactivation of CASP11, through an IFNAR1-dependent or IFNGR1-dependent mechanism initiated by TLR4 or IL18 signaling [620, 643, 644]”
From Molecular mechanisms of cell death: recommendations of the nomenclature committee on cell death 2018. (2018) · cites this paper as [643]
A limitation of the study is that the caspase-1-null mice were also found to be deficient in caspase-11.
“A limitation of our study is that the caspase-1–null mice were also found to be deficient in caspase-11 (46,47)”
From Sustained Inflammasome Activity in Macrophages Impairs Wound Healing in Type 2 Diabetic Humans and Mice (2014) · cites this paper as [47]
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- Authors
- Broz, P., Ruby, T., Belhocine, K., Bouley, D. M., Kayagaki, N., Dixit, V. M., & Monack, D. M.
- Affiliations
- Stanford Medicine (US)
- Genentech (US)
- Corresponding author
- Monack, Denise M.
- Venue
- Nature
- Published
- 2012-08-15
- Volume
- 490
- Issue
- 7419
- Pages
- 288-291
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC3470772
- OpenAlex
- W2024591203
- Cited by
- 535
- References
- 23
- Citations by year
- 2026: 13 · 2025: 25 · 2024: 20 · 2023: 35 · 2022: 33 · 2021: 31 · 2020: 47 · 2019: 40 · 2018: 38 · 2017: 40 · 2016: 51 · 2015: 49 · 2014: 53 · 2013: 53 · 2012: 6
- FWCI
- 20.71
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- National Institute of Allergy and Infectious Diseases (F32AI008972, AI095396, R01AI089722, AI08972, R01AI095396)
- 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 › Agricultural and Biological Sciences › Food Science › Salmonella and Campylobacter epidemiology
- Keywords
- caspase-11, caspase-1, Salmonella typhimurium, non-canonical inflammasome, macrophage cell death, pyroptosis, bacterial dissemination, innate immunity, TLR4, TRIF, NOD2, NOD-like receptors, IL-1β, IL-18
- MeSH terms
- Adjuvants, Immunologic, Animals, Cells, Cultured, Disease Susceptibility, Gene Expression Regulation, Interferon-gamma, Lipopolysaccharides, Macrophages, Salmonella Infections, Animal, Salmonella typhimurium, Signal Transduction, Cell Death, Mice, Knockout, Caspases, Mice, Caspases, Initiator, Inflammasomes
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