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Enhanced bacterial clearance and sepsis resistance in caspase-12-deficient mice

A Corrigendum to this article was published on 29 May 2013

This article has been updated

Abstract

Caspases function in both apoptosis and inflammatory cytokine processing and thereby have a role in resistance to sepsis1. Here we describe a novel role for a caspase in dampening responses to bacterial infection. We show that in mice, gene-targeted deletion of caspase-12 renders animals resistant to peritonitis and septic shock. The resulting survival advantage was conferred by the ability of the caspase-12-deficient mice to clear bacterial infection more efficiently than wild-type littermates. Caspase-12 dampened the production of the pro-inflammatory cytokines interleukin (IL)-1β, IL-18 (interferon (IFN)-γ inducing factor) and IFN-γ, but not tumour-necrosis factor-α and IL-6, in response to various bacterial components that stimulate Toll-like receptor and NOD pathways. The IFN-γ pathway was crucial in mediating survival of septic caspase-12-deficient mice, because administration of neutralizing antibodies to IFN-γ receptors ablated the survival advantage that otherwise occurred in these animals. Mechanistically, caspase-12 associated with caspase-1 and inhibited its activity. Notably, the protease function of caspase-12 was not necessary for this effect, as the catalytically inactive caspase-12 mutant Cys299Ala also inhibited caspase-1 and IL-1β production to the same extent as wild-type caspase-12. In this regard, caspase-12 seems to be the cFLIP counterpart for regulating the inflammatory branch of the caspase cascade. In mice, caspase-12 deficiency confers resistance to sepsis and its presence exerts a dominant-negative suppressive effect on caspase-1, resulting in enhanced vulnerability to bacterial infection and septic mortality.

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Figure 1: Casp12 -/- mice are resistant to sepsis and clear pathogens more efficiently than Casp12 +/+ mice.
Figure 2: Caspase-12 dampens production of cytokines essential for sepsis survival.
Figure 3: The catalytic function of caspase-12 is not required for its inhibitory effect on IL-1β production.
Figure 4: Caspase-12 as well as the catalytically inactive mutant Cys299Ala associate with caspase-1 and block its activity.

Change history

  • 29 May 2013

    Nature 440, 1064–1068 (2006); doi:10.1038/nature04656 Owing to an error in the production process, some details were omitted from the advance online publication version of this Corrigendum: this is the complete version. When our Letter was under consideration at Nature, we originally showed co-immunoprecipitation between caspase-1 and wild-type caspase-12 or catalytically inactive caspase-12 (C299A) as part of Fig.

References

  1. Hotchkiss, R. S. et al. Caspase inhibitors improve survival in sepsis: a critical role of the lymphocyte. Nature Immunol. 1, 496–501 (2000)

    Article  CAS  Google Scholar 

  2. Li, P. et al. Mice deficient in IL-1β-converting enzyme are defective in production of mature IL-1β and resistant to endotoxic shock. Cell 80, 401–411 (1995)

    Article  CAS  Google Scholar 

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

    Article  ADS  CAS  Google Scholar 

  4. Wang, S. et al. Murine caspase-11, an ICE-interacting protease, is essential for the activation of ICE. Cell 92, 501–509 (1998)

    Article  CAS  Google Scholar 

  5. Saleh, M. et al. Differential modulation of endotoxin responsiveness by human caspase-12 polymorphisms. Nature 429, 75–79 (2004)

    Article  ADS  CAS  Google Scholar 

  6. Zantl, N. et al. Essential role of gamma interferon in survival of colon ascendens stent peritonitis, a novel murine model of abdominal sepsis. Infect. Immun. 66, 2300–2309 (1998)

    Article  CAS  Google Scholar 

  7. Hotchkiss, R. S. et al. Adoptive transfer of apoptotic splenocytes worsens survival, whereas adoptive transfer of necrotic splenocytes improves survival in sepsis. Proc. Natl Acad. Sci. USA 100, 6724–6729 (2003)

    Article  ADS  CAS  Google Scholar 

  8. Prass, K. et al. Stroke-induced immunodeficiency promotes spontaneous bacterial infections and is mediated by sympathetic activation reversal by poststroke T helper cell type 1-like immunostimulation. J. Exp. Med. 198, 725–736 (2003)

    Article  CAS  Google Scholar 

  9. Rasper, D. M. et al. Cell death attenuation by ‘Usurpin’, a mammalian DED-caspase homologue that precludes caspase-8 recruitment and activation by the CD-95 (Fas, APO-1) receptor complex. Cell Death Differ. 5, 271–288 (1998)

    Article  CAS  Google Scholar 

  10. Irmler, M. et al. Inhibition of death receptor signals by cellular FLIP. Nature 388, 190–195 (1997)

    Article  ADS  CAS  Google Scholar 

  11. Martinon, F., Burns, K. & Tschopp, J. The inflammasome: a molecular platform triggering activation of inflammatory caspases and processing of proIL-β. Mol. Cell 10, 417–426 (2002)

    Article  CAS  Google Scholar 

  12. Joshi, V. D., Kalvakolanu, D. V., Hebel, J. R., Hasday, J. D. & Cross, A. S. Role of caspase 1 in murine antibacterial host defenses and lethal endotoxemia. Infect. Immun. 70, 6896–6903 (2002)

    Article  CAS  Google Scholar 

  13. Watanabe, T., Kitani, A., Murray, P. J. & Strober, W. NOD2 is a negative regulator of Toll-like receptor 2-mediated T helper type 1 responses. Nature Immunol. 5, 800–808 (2004)

    Article  CAS  Google Scholar 

  14. Kobayashi, K. S. et al. Nod2-dependent regulation of innate and adaptive immunity in the intestinal tract. Science 307, 731–734 (2005)

    Article  ADS  CAS  Google Scholar 

  15. Nakagawa, T. et al. Caspase-12 mediates endoplasmic reticulum-specific apoptosis and cytotoxicity by amyloid-β. Nature 403, 98–103 (2000)

    Article  ADS  CAS  Google Scholar 

  16. Kalai, M. et al. Regulation of the expression and processing of caspase-12. J. Cell Biol. 162, 457–467 (2003)

    Article  CAS  Google Scholar 

  17. Obeng, E. A. & Boise, L. H. Caspase-12 and caspase-4 are not required for caspase-dependent endoplasmic reticulum stress-induced apoptosis. J. Biol. Chem. 280, 29578–29587 (2005)

    Article  CAS  Google Scholar 

  18. Hitomi, J. et al. Involvement of caspase-4 in endoplasmic reticulum stress-induced apoptosis and Aβ-induced cell death. J. Cell Biol. 165, 347–356 (2004)

    Article  CAS  Google Scholar 

Download references

Acknowledgements

M.S. is supported by a CIHR post-doctoral fellowship. D.R.G. is supported by grants from the US NIH. We thank S. Granger and A. Coddington for help with the Bio-plex system and C. Bonzon for help with MEF preparation. Author Contributions D.R.G. and D.W.N. share senior authorship.

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Correspondence to Douglas R. Green or Donald W. Nicholson.

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D.W.N. is Vice-President of Merck Research Laboratories. It is highly unlikely, but possible, that D.W.N. or the company would gain or lose financially through publication of this paper.

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Supplementary Figures nature04656-s1.ppt This file contains Supplementary Figures 1–6. (PPT 5452 kb)

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This file contains text to accompany the above Supplementary Figures. (DOC 23 kb)

Supplementary Methods

This file contains additional details of the methods used in this study. (DOC 60 kb)

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Saleh, M., Mathison, J., Wolinski, M. et al. Enhanced bacterial clearance and sepsis resistance in caspase-12-deficient mice. Nature 440, 1064–1068 (2006). https://doi.org/10.1038/nature04656

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