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 journalArticleResearchpeer-review

126 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)2918-2926
Number of pages9
JournalEuropean Journal of Immunology
Volume45
Issue number10
DOIs
Publication statusPublished - Oct 2015
Externally publishedYes

Keywords

  • Caspase-4
  • Caspase-5
  • LPS
  • NLRP3 inflammasome
  • Pyroptosis

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