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Non-canonical inflammasome activation targets caspase-11

Nature volume 479, pages 117–121 (2011)Cite this article

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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)-1β and IL-18 during the innate immune response1,2,3,4,5. Here we show, with C57BL/6 Casp11 gene-targeted mice, that caspase-11 (also known as caspase-4)6,7,8 is critical for caspase-1 activation and IL-1β production in macrophages infected with Escherichia coli, Citrobacter rodentium or Vibrio cholerae. Strain 129 mice, like Casp11−/− mice, exhibited defects in IL-1β 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 cells9,10. 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-1β normally in response to ATP and monosodium urate, indicating that caspase-11 is engaged by a non-canonical inflammasome. Casp1–/–Casp11129mt/129mt macrophages expressing caspase-11 from a C57BL/6 bacterial artificial chromosome transgene failed to secrete IL-1β regardless of stimulus, confirming an essential role for caspase-1 in IL-1β 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.

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Figure 1: Germline mutation of Casp11 in mouse strain 129 abolishes inflammasome activation by CTB.
Figure 2: Caspase-11 mediates non-canonical inflammasome activation by CTB, E. coli, C. rodentium and V. cholerae.
Figure 3: Caspase-1 and caspase-11 have stimulus-specific roles during inflammasome activation.
Figure 4: Caspase-11 rather than caspase-1 is required for LPS-induced lethality.

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Acknowledgements

We thank F.-X. Blaudin de Thé, A. Paler Martinez, R. J. Newman, X. Rairdan, N. Ota, J. Ngo, L. Nguyen, A. Leung, L. Tam, M. Schlatter, H. Nguyen, V. Asghari and K. O’Rourke for technical support, M. van Lookeren Campagne, D. French, S. Mariathasan, T.-D. Kanneganti and D.M. Monack for discussion and reagents.

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Authors and Affiliations

  1. Department of Physiological Chemistry, Genentech Inc., South San Francisco, 94080, California, USA

    Nobuhiko Kayagaki, Salina Louie, Jennifer Dong, Kim Newton, Yan Qu & Vishva M. Dixit

  2. Department of Molecular Biology, Genentech Inc., South San Francisco, 94080, California, USA

    Søren Warming, Sherry Heldens & Merone Roose-Girma

  3. Department of Medical Protein Research, VIB, B-9000 Ghent, Belgium

    Mohamed Lamkanfi & Lieselotte Vande Walle

  4. Department of Biochemistry, Ghent University, B-9000 Ghent, Belgium

    Mohamed Lamkanfi & Lieselotte Vande Walle

  5. Department of Bioinformatics, Genentech Inc., South San Francisco, 94080, California, USA

    Jinfeng Liu

  6. Department of Immunology, Genentech Inc., South San Francisco, 94080, California, USA

    Juan Zhang & Wyne P. Lee

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  1. Nobuhiko Kayagaki
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Contributions

N.K., M.L., L.V.W., S.L., J.D., Y.Q. and S.H. designed and performed in vitro experiments. N.K., S.L., J.D., J.Z. and W.P.L. designed and performed in vivo experiments. S.W., M.R.-G. and K.N. generated the Casp11–/– and Casp1–/–Casp11Tg mice. J.L. performed bioinformatics analyses. N.K., S.W., K.N. and V.M.D. prepared the manuscript. N.K. and V.M.D. contributed to the study design and data analyses.

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Correspondence to Nobuhiko Kayagaki or Vishva M. Dixit.

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Most authors were employees of Genentech, Inc.

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Kayagaki, N., Warming, S., Lamkanfi, M. et al. Non-canonical inflammasome activation targets caspase-11. Nature 479, 117–121 (2011). https://doi.org/10.1038/nature10558

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