TY - JOUR
T1 - Proteasome inhibitors prevent caspase-1-mediated disease in rodents challenged with anthrax lethal toxin
AU - Muehlbauer, Stefan M.
AU - Lima, Heriberto
AU - Goldman, David L.
AU - Jacobson, Lee S.
AU - Rivera, Johanna
AU - Goldberg, Michael F.
AU - Palladino, Michael A.
AU - Casadevall, Arturo
AU - Brojatsch, Jürgen
N1 - Funding Information:
Supported in part by the grant 5U54AI057158-05 from the Northeastern Biodefense Center (D.L.G. and A.C.), by the NIH Medical Scientist Training grant T32GM007288 (S.M.M.), and by a grant (NIAID-AI075222-01A1 to J.B.) from the National Institute of Allergy and Infectious Disease.
PY - 2010/8
Y1 - 2010/8
N2 - 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.
AB - 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.
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U2 - 10.2353/ajpath.2010.090828
DO - 10.2353/ajpath.2010.090828
M3 - Article
C2 - 20595632
AN - SCOPUS:77957279148
SN - 0002-9440
VL - 177
SP - 735
EP - 743
JO - American Journal of Pathology
JF - American Journal of Pathology
IS - 2
ER -