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

Maya Saleh, John C. Mathison, Melissa K. Wolinski, Steve J. Bensinger, Patrick Fitzgerald, Nathalie Droin, Richard J. Ulevitch, Douglas R. Green, Donald W. Nicholson

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285 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)1064-1068
Number of pages5
JournalNature
Volume440
Issue number7087
DOIs
Publication statusPublished - 20 Apr 2006
Externally publishedYes

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