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Non-canonical inflammasome activation targets caspase-11

(2011) NATURE. 479(7371). p.117-U146
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Abstract
Caspase-1 activation by inflammasome scaffolds comprised of intracellular nucleotide-binding oligomerization domain (NOD)-like receptors (NLRs) and the adaptor ASC is believed to be essential for production of the pro-inflammatory cytokines interleukin (IL)-1 beta and IL-18 during the innate immune response(1-5). Here we show, with C57BL/6 Casp11 gene-targeted mice, that caspase-11 (also known as caspase-4)(6-8) is critical for caspase-1 activation and IL-1 beta production in macrophages infected with Escherichia coli, Citrobacter rodentium or Vibrio cholerae. Strain 129 mice, like Casp11(-/-) mice, exhibited defects in IL-1 beta production and harboured a mutation in the Casp11 locus that attenuated caspase-11 expression. This finding is important because published targeting of the Casp1 gene was done using strain 129 embryonic stem cells(9,10). Casp1 and Casp11 are too close in the genome to be segregated by recombination; consequently, the published Casp1(-/-) mice lack both caspase-11 and caspase-1. Interestingly, Casp11(-/-) macrophages secreted IL-1 beta normally in response to ATP and monosodium urate, indicating that caspase-11 is engaged by a non-canonical inflammasome. Casp1(-/-)Casp11(129mt/129mt) macrophages expressing caspase-11 from a C57BL/6 bacterial artificial chromosome transgene failed to secrete IL-1 beta regardless of stimulus, confirming an essential role for caspase-1 in IL-1 beta production. Caspase-11 rather than caspase-1, however, was required for non-canonical inflammasome-triggered macrophage cell death, indicating that caspase-11 orchestrates both caspase-1-dependent and -independent outputs. Caspase-1 activation by non-canonical stimuli required NLRP3 and ASC, but caspase-11 processing and cell death did not, implying that there is a distinct activator of caspase-11. Lastly, loss of caspase-11 rather than caspase-1 protected mice from a lethal dose of lipopolysaccharide. These data highlight a unique pro-inflammatory role for caspase-11 in the innate immune response to clinically significant bacterial infections.
Keywords
RESPONSES, APOPTOSIS, RECEPTORS, IL-1-BETA, RECOGNITION, MICE DEFICIENT, NLRP3 INFLAMMASOME, ANTHRAX LETHAL TOXIN, GAMMA-INDUCING FACTOR, INTERLEUKIN-1-BETA CONVERTING-ENZYME

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Citation

Please use this url to cite or link to this publication:

MLA
Kayagaki, Nobuhiko, Soren Warming, Mohamed Lamkanfi, et al. “Non-canonical Inflammasome Activation Targets Caspase-11.” NATURE 479.7371 (2011): 117–U146. Print.
APA
Kayagaki, N., Warming, S., Lamkanfi, M., Vande Walle, L., Louie, S., Dong, J., Newton, K., et al. (2011). Non-canonical inflammasome activation targets caspase-11. NATURE, 479(7371), 117–U146.
Chicago author-date
Kayagaki, Nobuhiko, Soren Warming, Mohamed Lamkanfi, Lieselotte Vande Walle, Salina Louie, Jennifer Dong, Kim Newton, et al. 2011. “Non-canonical Inflammasome Activation Targets Caspase-11.” Nature 479 (7371): 117–U146.
Chicago author-date (all authors)
Kayagaki, Nobuhiko, Soren Warming, Mohamed Lamkanfi, Lieselotte Vande Walle, Salina Louie, Jennifer Dong, Kim Newton, Yan Qu, JinFeng Liu, Sherry Heldens, Juan Zhang, Wyne P Lee, Merone Roose-Girma, and Vishva M Dixit. 2011. “Non-canonical Inflammasome Activation Targets Caspase-11.” Nature 479 (7371): 117–U146.
Vancouver
1.
Kayagaki N, Warming S, Lamkanfi M, Vande Walle L, Louie S, Dong J, et al. Non-canonical inflammasome activation targets caspase-11. NATURE. 2011;479(7371):117–U146.
IEEE
[1]
N. Kayagaki et al., “Non-canonical inflammasome activation targets caspase-11,” NATURE, vol. 479, no. 7371, pp. 117-U146, 2011.
@article{1956055,
  abstract     = {Caspase-1 activation by inflammasome scaffolds comprised of intracellular nucleotide-binding oligomerization domain (NOD)-like receptors (NLRs) and the adaptor ASC is believed to be essential for production of the pro-inflammatory cytokines interleukin (IL)-1 beta and IL-18 during the innate immune response(1-5). Here we show, with C57BL/6 Casp11 gene-targeted mice, that caspase-11 (also known as caspase-4)(6-8) is critical for caspase-1 activation and IL-1 beta production in macrophages infected with Escherichia coli, Citrobacter rodentium or Vibrio cholerae. Strain 129 mice, like Casp11(-/-) mice, exhibited defects in IL-1 beta production and harboured a mutation in the Casp11 locus that attenuated caspase-11 expression. This finding is important because published targeting of the Casp1 gene was done using strain 129 embryonic stem cells(9,10). Casp1 and Casp11 are too close in the genome to be segregated by recombination; consequently, the published Casp1(-/-) mice lack both caspase-11 and caspase-1. Interestingly, Casp11(-/-) macrophages secreted IL-1 beta normally in response to ATP and monosodium urate, indicating that caspase-11 is engaged by a non-canonical inflammasome. Casp1(-/-)Casp11(129mt/129mt) macrophages expressing caspase-11 from a C57BL/6 bacterial artificial chromosome transgene failed to secrete IL-1 beta regardless of stimulus, confirming an essential role for caspase-1 in IL-1 beta production. Caspase-11 rather than caspase-1, however, was required for non-canonical inflammasome-triggered macrophage cell death, indicating that caspase-11 orchestrates both caspase-1-dependent and -independent outputs. Caspase-1 activation by non-canonical stimuli required NLRP3 and ASC, but caspase-11 processing and cell death did not, implying that there is a distinct activator of caspase-11. Lastly, loss of caspase-11 rather than caspase-1 protected mice from a lethal dose of lipopolysaccharide. These data highlight a unique pro-inflammatory role for caspase-11 in the innate immune response to clinically significant bacterial infections.},
  author       = {Kayagaki, Nobuhiko and Warming, Soren and Lamkanfi, Mohamed and Vande Walle, Lieselotte and Louie, Salina and Dong, Jennifer and Newton, Kim and Qu, Yan and Liu, JinFeng and Heldens, Sherry and Zhang, Juan and Lee, Wyne P and Roose-Girma, Merone and Dixit, Vishva M},
  issn         = {0028-0836},
  journal      = {NATURE},
  keywords     = {RESPONSES,APOPTOSIS,RECEPTORS,IL-1-BETA,RECOGNITION,MICE DEFICIENT,NLRP3 INFLAMMASOME,ANTHRAX LETHAL TOXIN,GAMMA-INDUCING FACTOR,INTERLEUKIN-1-BETA CONVERTING-ENZYME},
  language     = {eng},
  number       = {7371},
  pages        = {117--U146},
  title        = {Non-canonical inflammasome activation targets caspase-11},
  url          = {http://dx.doi.org/10.1038/nature10558},
  volume       = {479},
  year         = {2011},
}

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