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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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.
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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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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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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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DOI: https://doi.org/10.1038/nature04656
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