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

Paul J Baker, Dave Boucher, Damien Bierschenk, Christina Tebartz, Paul G Whitney, Damian B D'Silva, Maria C Tanzer, Mercedes Monteleone, Avril A B Robertson, Matthew A Cooper, Silvia Alvarez-Diaz, Marco J Herold, Sammy Bedoui, Kate Schroder, Seth L Masters

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish
Pages (from-to) 2918-2926
Number of pages9
JournalEuropean Journal of Immunology
Issue number10
Publication statusPublished - 6 Oct 2015

Bibliographical note

© 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.


  • Carrier Proteins/immunology
  • Caspases/immunology
  • Caspases, Initiator/immunology
  • Cell Line, Tumor
  • Humans
  • Interleukin-1beta/immunology
  • Lipopolysaccharides/immunology
  • Monocytes/immunology
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • Salmonella Infections/immunology
  • Salmonella typhimurium/immunology

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