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


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.


  1. Schroder, K. & Tschopp, J. The inflammasomes. Cell 140, 821–832 (2010)

    Article  CAS  Google Scholar 

  2. Lamkanfi, M. Emerging inflammasome effector mechanisms. Nature Rev. Immunol. 11, 213–220 (2011)

    Article  CAS  Google Scholar 

  3. Kayagaki, N. et al. Non-canonical inflammasome activation targets caspase-11. Nature 479, 117–121 (2011)

    Article  CAS  ADS  Google Scholar 

  4. Wang, S. et al. Identification and characterization of Ich-3, a member of the interleukin-1β converting enzyme (ICE)/Ced-3 family and an upstream regulator of ICE. J. Biol. Chem. 271, 20580–20587 (1996)

    Article  CAS  Google Scholar 

  5. Kang, S. J. et al. Dual role of caspase-11 in mediating activation of caspase-1 and caspase-3 under pathological conditions. J. Cell Biol. 149, 613–622 (2000)

    Article  CAS  Google Scholar 

  6. Kuida, K. et al. Altered cytokine export and apoptosis in mice deficient in interleukin-1β converting enzyme. Science 267, 2000–2003 (1995)

    Article  CAS  ADS  Google Scholar 

  7. Lara-Tejero, M. et al. Role of the caspase-1 inflammasome in Salmonella typhimurium pathogenesis. J. Exp. Med. 203, 1407–1412 (2006)

    Article  CAS  Google Scholar 

  8. Raupach, B., Peuschel, S. K., Monack, D. M. & Zychlinsky, A. Caspase-1-mediated activation of interleukin-1β (IL-1β) and IL-18 contributes to innate immune defenses against Salmonella enterica serovar Typhimurium infection. Infect. Immun. 74, 4922–4926 (2006)

    Article  CAS  Google Scholar 

  9. Mariathasan, S. et al. Differential activation of the inflammasome by caspase-1 adaptors ASC and Ipaf. Nature 430, 213–218 (2004)

    Article  CAS  ADS  Google Scholar 

  10. Broz, P. et al. Redundant roles for inflammasome receptors NLRP3 and NLRC4 in host defense against Salmonella. J. Exp. Med. 207, 1745–1755 (2010)

    Article  CAS  Google Scholar 

  11. Monack, D. M., Detweiler, C. S. & Falkow, S. Salmonella pathogenicity island 2-dependent macrophage death is mediated in part by the host cysteine protease caspase-1. Cell Microbiol. 3, 825–837 (2001)

    Article  CAS  Google Scholar 

  12. Akhter, A. et al. Caspase-11 promotes the fusion of phagosomes harboring pathogenic bacteria with lysosomes by modulating actin polymerization. Immunity (31 May 2012)

  13. Miao, E. A. et al. Cytoplasmic flagellin activates caspase-1 and secretion of interleukin 1β via Ipaf. Nature Immunol. 7, 569–575 (2006)

    Article  CAS  Google Scholar 

  14. Franchi, L. et al. Cytosolic flagellin requires Ipaf for activation of caspase-1 and interleukin 1β in Salmonella-infected macrophages. Nature Immunol. 7, 576–582 (2006)

    Article  CAS  Google Scholar 

  15. Kofoed, E. M. & Vance, R. E. Innate immune recognition of bacterial ligands by NAIPs determines inflammasome specificity. Nature 474, 592–595 (2011)

    Article  ADS  Google Scholar 

  16. Zhao, Y. et al. The NLRC4 inflammasome receptors for bacterial flagellin and type III secretion apparatus. Nature 477, 596–600 (2011)

    Article  CAS  ADS  Google Scholar 

  17. Schauvliege, R., Vanrobaeys, J., Schotte, P. & Beyaert, R. Caspase-11 gene expression in response to lipopolysaccharide and interferon-gamma requires nuclear factor-κB and signal transducer and activator of transcription (STAT) 1. J. Biol. Chem. 277, 41624–41630 (2002)

    Article  CAS  Google Scholar 

  18. O’'Neill, L. A. & Bowie, A. G. The family of five: TIR-domain-containing adaptors in Toll-like receptor signalling. Nature Rev. Immunol. 7, 353–364 (2007)

    Article  Google Scholar 

  19. Franchi, L., Munoz-Planillo, R. & Nunez, G. Sensing and reacting to microbes through the inflammasomes. Nature Immunol. 13, 325–332 (2012)

    Article  CAS  Google Scholar 

  20. Conlan, J. W. Critical roles of neutrophils in host defense against experimental systemic infections of mice by Listeria monocytogenes, Salmonella typhimurium, and Yersinia enterocolitica. Infect. Immun. 65, 630–635 (1997)

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Valdez, Y., Ferreira, R. B. & Finlay, B. B. Molecular mechanisms of Salmonella virulence and host resistance. Curr. Top. Microbiol. Immunol. 337, 93–127 (2009)

    CAS  PubMed  Google Scholar 

  22. Miao, E. A. et al. Caspase-1-induced pyroptosis is an innate immune effector mechanism against intracellular bacteria. Nature Immunol. 11, 1136–1142 (2010)

    Article  CAS  Google Scholar 

  23. Conlan, J. W. Neutrophils prevent extracellular colonization of the liver microvasculature by Salmonella typhimurium. Infect. Immun. 64, 1043–1047 (1996)

    CAS  PubMed  PubMed Central  Google Scholar 

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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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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).

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