Enhanced bacterial clearance and sepsis resistance in caspase-12-deficient mice.
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)-1beta, IL-18 (interferon (IFN)-gamma inducing factor) and IFN-gamma, but not tumour-necrosis factor-alpha and IL-6, in response to various bacterial components that stimulate Toll-like receptor and NOD pathways. The IFN-gamma pathway was crucial in mediating survival of septic caspase-12-deficient mice, because administration of neutralizing antibodies to IFN-gamma 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-1beta 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.
Saleh
Maya
M
Department of Cellular Immunology, La Jolla Institute for Allergy and Immunology, San Diego, California 92121, USA.
Mathison
John C
JC
Wolinski
Melissa K
MK
Bensinger
Steve J
SJ
Fitzgerald
Patrick
P
Droin
Nathalie
N
Ulevitch
Richard J
RJ
Green
Douglas R
DR
Nicholson
Donald W
DW
D000818:Animals; D020170:Caspase 1 / Q000378:metabolism; D053454:Caspase 12; D061945:Caspase Inhibitors; D020169:Caspases / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism*; D002384:Catalysis; D002460:Cell Line; D004198:Disease Susceptibility / Q000201:enzymology / Q000276:immunology / Q000382:microbiology; D006801:Humans; D007371:Interferon-gamma / Q000276:immunology / Q000378:metabolism; D007375:Interleukin-1 / Q000096:biosynthesis / Q000276:immunology / Q000378:metabolism; D020382:Interleukin-18 / Q000276:immunology / Q000378:metabolism; D008089:Listeria monocytogenes / Q000276:immunology* / Q000302:isolation & purification / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D010538:Peritonitis / Q000201:enzymology / Q000276:immunology / Q000382:microbiology; D011485:Protein Binding; D018805:Sepsis / Q000201:enzymology / Q000276:immunology* / Q000382:microbiology*; D012772:Shock, Septic / Q000201:enzymology / Q000276:immunology / Q000382:microbiology; D015996:Survival Rate
D061945:Caspase Inhibitors; D007375:Interleukin-1; D020382:Interleukin-18; D007371:Interferon-gamma; C506444:CASP12 protein, human; C506440:Casp12 protein, mouse; D053454:Caspase 12; D020169:Caspases; D020170:Caspase 1