NLRP3 inflammasome activation downstream of cytoplasmic LPS recognition by both caspase-4 and caspase-5
- Baker, PJ; Boucher, D; Bierschenk, D; Tebartz, C; Whitney, PG; D'Silva, DB; Tanzer, MC; Monteleone, M; Robertson, AA; Cooper, MA; Alvarez-Diaz, S; Herold, MJ; Bedoui, S; Schroder, K; Masters, SL;
Publication Year 2018, Volume 200, Issue #10, Page 3341-3346
- Journal Title
- European Journal of Immunology
- Publication Type
- Journal Article
- Humans encode two inflammatory caspases that detect cytoplasmic LPS, caspase-4 and caspase-5. When activated, these trigger pyroptotic cell death and caspase-1-dependent IL-1beta production, however the mechanism underlying this process is not yet confirmed. We now show that a specific NLRP3 inhibitor, MCC950, prevents caspase-4/5-dependent IL-1beta production elicited by transfected LPS. Given that caspase-4 and caspase-5 can both detect cytoplasmic LPS, it is possible that these proteins exhibit some degree of redundancy. Therefore we generated human monocytic cell lines in which caspase-4 and caspase-5 were genetically deleted either individually or together. We found that the deletion of caspase-4 suppressed cell death and IL-1beta production following transfection of LPS into the cytoplasm, or in response to infection with Salmonella Typhimurium. Although deletion of caspase-5 did not confer protection against transfected LPS, cell death and IL-1beta production were reduced after infection with Salmonella. Furthermore, double deletion of caspase-4 and -5 had a synergistic effect in the context of Salmonella infection. Our results identify the NLRP3 inflammasome as the specific platform for IL-1beta maturation, downstream of cytoplasmic LPS detection by caspase-4/5. We also show that both caspase-4 and caspase-5 are functionally important for appropriate responses to intracellular Gram-negative bacteria. This article is protected by copyright. All rights reserved.
- WEHI Research Division(s)
- Inflammation; Molecular Genetics Of Cancer; Cell Signalling And Cell Death
- PubMed ID
- Publisher's Version
- NHMRC Grants
- Rights Notice
- Refer to copyright notice on published article.
Creation Date: 2015-07-20 02:23:54Last Modified: 2018-06-05 01:41:48