title: Anthrax lethal toxin activates the inflammasome in sensitive rat macrophages.
abstract: Anthrax lethal toxin (LT) is an important virulence factor for Bacillus anthracis. In mice, LT lyses macrophages from certain inbred strains in less than 2h by activating the Nlrp1b inflammasome and caspase-1, while macrophages from other strains remain resistant to the toxin's effects. We analyzed LT effects in toxin-sensitive and resistant rat macrophages to test if a similar pathway was involved in rat macrophage death. LT activates caspase-1 in rat macrophages from strains harboring LT-sensitive macrophages in a manner similar to that in toxin-sensitive murine macrophages. This activation of caspase-1 is dependent on proteasome activity, and sensitive macrophages are protected from LT's lytic effects by lactacystin. Proteasome inhibition also delayed the death of rats in response to LT, confirming our previous data implicating the rat Nlrp1 inflammasome in animal death. Quinidine, caspase-1 inhibitors, the cathepsin B inhibitor CA-074Me, and heat shock also protected rat macrophages from LT toxicity. These data support the existence of an active functioning LT-responsive Nlrp1 inflammasome in rat macrophages. The activation of the rat Nlrp1 inflammasome is required for LT-mediated rat macrophage lysis and contributes to animal death.
authors.affiliation: Laboratory of Bacterial Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, 33 North Drive, Building 33, Room 1W20B, Bethesda, MD 20892, USA. newmanz@niaid.nih.gov
authors.forename: Zachary L
authors.initials: ZL
authors.lastname: Newman
authors.forename: Devorah
authors.initials: D
authors.lastname: Crown
authors.forename: Stephen H
authors.initials: SH
authors.lastname: Leppla
authors.forename: Mahtab
authors.initials: M
authors.lastname: Moayeri
mesh_terms: D000111:Acetylcysteine / Q000031:analogs & derivatives / Q000494:pharmacology; D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D000942:Antigens, Bacterial / Q000633:toxicity*; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism*; D001427:Bacterial Toxins / Q000633:toxicity*; D020170:Caspase 1 / Q000378:metabolism; D016923:Cell Death; D002460:Cell Line; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D005260:Female; D007249:Inflammation / Q000235:genetics / Q000378:metabolism*; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D051381:Rats
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000942:Antigens, Bacterial; D051017:Apoptosis Regulatory Proteins; D001427:Bacterial Toxins; D015853:Cysteine Proteinase Inhibitors; C529636:NALP1 protein, mouse; C030325:anthrax toxin; C067713:lactacystin; D020170:Caspase 1; D046988:Proteasome Endopeptidase Complex; D000111:Acetylcysteine