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

• Published in: Nature 2006-04, Vol.440 (7087), p.1064-1068
• Main Authors: Green, Douglas R, Nicholson, Donald W, Saleh, Maya, Mathison, John C, Wolinski, Melissa K, Bensinger, Steve J, Fitzgerald, Patrick, Droin, Nathalie, Ulevitch, Richard J
• Format: Article
• Language: English
• Subjects: Animals; Apoptosis; Bacteria; Bacterial diseases; Bacterial growth; Bacteriology; Biological and medical sciences; Caspase 1 - metabolism; Caspase 12; Caspase Inhibitors; Caspases; Caspases - deficiency; Caspases - genetics; Caspases - metabolism; Catalysis; Cell Line; Control; Cytokines; Disease Susceptibility - enzymology; Disease Susceptibility - immunology; Disease Susceptibility - microbiology; Fundamental and applied biological sciences. Psychology; Health aspects; Humanities and Social Sciences; Humans; Interferon-gamma - immunology; Interferon-gamma - metabolism; Interleukin-1 - biosynthesis; Interleukin-1 - immunology; Interleukin-1 - metabolism; Interleukin-18 - immunology; Interleukin-18 - metabolism; letter; Listeria monocytogenes - immunology; Listeria monocytogenes - isolation & purification; Listeria monocytogenes - physiology; Mice; Mice, Knockout; Microbiology; Mortality; multidisciplinary; Mutation; Pathogenicity, virulence, toxins, bacteriocins, pyrogens, host-bacteria relations, miscellaneous strains; Peritonitis - enzymology; Peritonitis - immunology; Peritonitis - microbiology; Prevention; Protein Binding; Rodents; Science; Sepsis; Sepsis - enzymology; Sepsis - immunology; Sepsis - microbiology; Shock, Septic - enzymology; Shock, Septic - immunology; Shock, Septic - microbiology; Survival; Survival Rate
• ISSN: 0028-0836; 1476-4687; 1476-4679
• DOI: 10.1038/nature04656

Caspases function in both apoptosis and inflammatory cytokine processing and thereby have a role in resistance to sepsis. 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.