Proteasome inhibitors prevent caspase-1-mediated disease in rodents challenged with anthrax lethal toxin.
NOD-like receptors (NLRs) and caspase-1 are critical components of innate immunity, yet their over-activation has been linked to a long list of microbial and inflammatory diseases, including anthrax. The Bacillus anthracis lethal toxin (LT) has been shown to activate the NLR Nalp1b and caspase-1 and to induce many symptoms of the anthrax disease in susceptible murine strains. In this study we tested whether it is possible to prevent LT-mediated disease by pharmacological inhibition of caspase-1. We found that caspase-1 and proteasome inhibitors blocked LT-mediated caspase-1 activation and cytolysis of LT-sensitive (Fischer and Brown-Norway) rat macrophages. The proteasome inhibitor NPI-0052 also prevented disease progression and death in susceptible Fischer rats and increased survival in BALB/c mice after LT challenge. In addition, NPI-0052 blocked rapid disease progression and death in susceptible Fischer rats and BALB/c mice challenged with LT. In contrast, Lewis rats, which harbor LT-resistant macrophages, showed no signs of caspase-1 activation after LT injection and did not exhibit rapid disease progression. Taken together, our findings indicate that caspase-1 activation is critical for rapid disease progression in rodents challenged with LT. Our studies indicate that pharmacological inhibition of NLR signaling and caspase-1 can be used to treat inflammatory diseases.
Muehlbauer
Stefan M
SM
Albert Einstein College of Medicine, Department of Microbiology and Immunology, Bronx, NY 10461, USA.
Lima
Heriberto
H
Goldman
David L
DL
Jacobson
Lee S
LS
Rivera
Johanna
J
Goldberg
Michael F
MF
Palladino
Michael A
MA
Casadevall
Arturo
A
Brojatsch
Jürgen
J
D000818:Animals; D000881:Anthrax / Q000378:metabolism*; D000942:Antigens, Bacterial / Q000378:metabolism*; D001408:Bacillus anthracis / Q000472:pathogenicity; D001427:Bacterial Toxins / Q000378:metabolism*; D020170:Caspase 1 / Q000378:metabolism*; D061945:Caspase Inhibitors; D016923:Cell Death; D002478:Cells, Cultured; D004789:Enzyme Activation; D008264:Macrophages / Q000166:cytology / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D061988:Proteasome Inhibitors; D051381:Rats; D011919:Rats, Inbred Strains
D000942:Antigens, Bacterial; D001427:Bacterial Toxins; D061945:Caspase Inhibitors; D061988:Proteasome Inhibitors; C030325:anthrax toxin; D020170:Caspase 1