NLRP3 inflammasome activation downstream of cytoplasmic LPS recognition by both caspase‐4 and caspase‐5

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,...

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Published inEuropean journal of immunology Vol. 45; no. 10; pp. 2918 - 2926
Main 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.
Format Journal Article
LanguageEnglish
Published Germany Wiley Subscription Services, Inc 01.10.2015
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Summary: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.
Bibliography:See accompanying Commentary by Rivers‐Auty and Brough
http://dx.doi.org/10.1002/eji.201545523
These authors contributed equally to this work.
http://dx.doi.org/10.1002/eji.201545772
See accompanying articles
See accompanying article by Sebastian Rühl and Petr Broz and Schmid‐Burgk et al.
:
http://dx.doi.org/10.1002/eji.201545958
See accompanying Commentary
ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
content type line 23
ISSN:0014-2980
1521-4141
DOI:10.1002/eji.201545655