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Caspase-11 increases susceptibility to Salmonella infection in the absence of caspase-1

Nature volume 490, pages 288–291 (2012)Cite this article

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Abstract

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 pyroptosis2. Recently, a new non-canonical inflammasome was described that activates caspase-11, a pro-inflammatory caspase required for lipopolysaccharide-induced lethality3. 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 knockouts3,4,5,6. Previous studies have shown that these mice are more susceptible to infections with microbial pathogens1, including the bacterial pathogen Salmonella enterica serovar Typhimurium (S. typhimurium)7,8, 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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Figure 1: Signalling through TLR4 and TRIF is required for activity of the non-canonical inflammasome pathway.
Figure 2: Type-I IFN signalling is required for caspase-11 activation, but not for pro-caspase-11 expression.
Figure 3: Casp1 −/− mice are more susceptible to Salmonella infection than Casp1 −/−  Casp11 −/− mice.

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Acknowledgements

We thank J. Dong, M. Wong, P. Chu and H. Matthew for technical support, G. Barton for Tlr4−/− and Tlr2−/− mice, and all members of the Monack laboratory for discussions and help with animal experiments. This work was supported by awards AI095396 and AI08972 from the National Institute of Allergy and Infectious Diseases (NIAID) to D.M.M., a Stanford Digestive Disease Center (DDC) pilot grant to P.B. and a long-term fellowship (LT000636/2009-L) from the Human Frontiers in Science Program (HFSP) to P.B.

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Authors and Affiliations

  1. Department of Microbiology and Immunology, Stanford School of Medicine, Stanford University, 94305, California, USA

    Petr Broz, Thomas Ruby, Kamila Belhocine & Denise M. Monack

  2. Department of Comparative Medicine Stanford School of Medicine, Stanford University, 94305, California, USA

    Donna M. Bouley

  3. Genentech Inc., South San Francisco, 94080, California, USA

    Nobuhiko Kayagaki & Vishva M. Dixit

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  1. Petr Broz
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Contributions

P.B., K.B. and D.M.M. designed and performed the in vitro experiments; P.B., K.B., T.R. and D.M.M. designed and performed the in vivo experiments; D.M.B. performed histological analysis, N.K. and V.M.D. contributed reagents and mice; all authors analysed data and wrote the manuscript.

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Correspondence to Denise M. Monack.

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N.K. and V.M.D are employees of Genentech Inc.

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Broz, P., Ruby, T., Belhocine, K. et al. Caspase-11 increases susceptibility to Salmonella infection in the absence of caspase-1. Nature 490, 288–291 (2012). https://doi.org/10.1038/nature11419

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