2. Academic Validation
  3. NLRP3 inflammasome activation downstream of cytoplasmic LPS recognition by both caspase-4 and caspase-5

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

  • Eur J Immunol. 2015 Oct;45(10):2918-26. doi: 10.1002/eji.201545655.
Paul J Baker 1 2,  Dave Boucher 3,  Damien Bierschenk 3,  Christina Tebartz 4 5,  Paul G Whitney 4 5,  Damian B D'Silva 1 2,  Maria C Tanzer 2 6,  Mercedes Monteleone 3,  Avril A B Robertson 3,  Matthew A Cooper 3,  Silvia Alvarez-Diaz 2 7,  Marco J Herold 2 7,  Sammy Bedoui 4 5,  Kate Schroder 3,  Seth L Masters 1 2
Affiliations

Affiliations

  • 1 Inflammation Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Australia.
  • 2 Department of Medical Biology, The University of Melbourne, Parkville, Australia.
  • 3 Cell Biology and Molecular Medicine Division, Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland, Australia.
  • 4 The Peter Doherty Institute for Infection and Immunity, Melbourne, Victoria, Australia.
  • 5 Department of Microbiology and Immunology, The University of Melbourne, Parkville, Australia.
  • 6 Cell Signaling and Cell Death Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Australia.
  • 7 Molecular Genetics of Cancer Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Australia.
PMID: 26173988 DOI: 10.1002/eji.201545655
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.

Keywords

Caspase-4; Caspase-5; LPS; NLRP3 inflammasome; Pyroptosis.

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