Proteasome inhibitors prevent caspase-1-mediated disease in rodents challenged with anthrax lethal toxin

Stefan M. Muehlbauer, Heriberto Lima, David L. Goldman, Lee S. Jacobson, Johanna Rivera, Michael F. Goldberg, Michael A. Palladino, Arturo Casadevall, Jürgen Brojatsch

Research output: Contribution to journalArticle

16 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)735-743
Number of pages9
JournalAmerican Journal of Pathology
Volume177
Issue number2
DOIs
Publication statusPublished - Aug 2010

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ASJC Scopus subject areas

  • Pathology and Forensic Medicine

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