Proteasome Inhibitors Prevent Caspase-1-Mediated Disease in Rodents Challenged with Anthrax Lethal Toxin

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.

Inflammasomes and Their Roles in Health and Disease

“…Inhibition of p38 and Akt was recently suggested to trigger ATP release through connexin-43 channels, which in turn causes K + efflux and Nlrp1b activation downstream of the purinergic P2X 7 receptor (Ali et al 2011). Ca 2+ fluxes and proteasome activation were also proposed to act upstream of Nlrp1b activation (Fink et al 2008, Muehlbauer et al 2010, Wickliffe et al 2008). Finally, LF-induced activation of Nlrp1b was suggested to involve cleavage of a currently unknown host factor by cathepsin B released from destabilized lysosomes (Newman et al 2009).…”

Distinct cathepsins control necrotic cell death mediated by pyroptosis inducers and lysosome-destabilizing agents

“…17 However, recent studies indicate that necrotic cell death is, like apoptosis, controlled by inducer-specific cellular factors and susceptible to distinct inhibitors. 5,8,28,41,55 In contrast to a multistep cascade driving apoptotic cell death, only single, inducer-specific events have been associated with necrotic cell death. For example, caspase-1 activation has been shown to drive pyroptosis, the best-studied form of necrotic cell death.…”

Platelet-activating Factor Contributes to Bacillus anthracis Lethal Toxin-associated Damage

“…The pattern of LeTx-induced macrophage death has been related to polymorphisms in Nalp1b and the macrophage activation state (33). Typically, macrophages from sensitive BALB/c mice undergo lysis and not apoptosis in response to LeTx (35,44), although apoptosis may occur in the context of sublytic levels of toxin (45). Endothelial cell apoptosis has also been described in HUVEC cells by some but not all investigators (38,39,46).…”