NLRP3 inflammasome activation downstream of cytoplasmic LPS recognition by both caspase-4 and caspase-5 Academic Article uri icon

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.

authors

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

publication date

  • 2015