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- Title
NLRP3 inflammasome activation downstream of cytoplasmic LPS recognition by both caspase-4 and caspase-5.
- Authors
Baker, Paul J.; Boucher, Dave; Bierschenk, Damien; Tebartz, Christina; Whitney, Paul G.; D'Silva, Damian B.; Tanzer, Maria C.; Monteleone, Mercedes; Robertson, Avril A. B.; Cooper, Matthew A.; Alvarez‐Diaz, Silvia; Herold, Marco J.; Bedoui, Sammy; Schroder, Kate; Masters, Seth L.
- Abstract
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-1β 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-1β production elicited by transfected LPS. Given that both caspase-4 and caspase-5 can 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-1β 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-1β production were reduced after infection with Salmonella. Furthermore, double deletion of caspase-4 and caspase-5 had a synergistic effect in the context of Salmonella infection. Our results identify the NLRP3 inflammasome as the specific platform for IL-1β 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.
- Publication
European Journal of Immunology, 2015, Vol 45, Issue 10, p2918
- ISSN
0014-2980
- Publication type
Article
- DOI
10.1002/eji.201545655