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

Author information

Affiliations

  • 1. Inflammation Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Australia.
      Authors
    • Baker PJ 1, 4
    • D'Silva DB 1, 4
    • Masters SL 1, 4
    (3 authors)
  • 2. Cell Biology and Molecular Medicine Division, Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland, Australia.
      Authors
    • Boucher D 2
    • Bierschenk D 2
    • Monteleone M 2
    • Robertson AA 2
    • Cooper MA 2
    • Schroder K 2
    (6 authors)
  • 3. The Peter Doherty Institute for Infection and Immunity, Melbourne, Victoria, Australia.
      Authors
    • Tebartz C 3
    • Whitney PG 3
    • Bedoui S 3
    (3 authors)
  • 4. Department of Medical Biology, The University of Melbourne, Parkville, Australia.
      Authors
    • Baker PJ 1, 4
    • D'Silva DB 1, 4
    • Tanzer MC 4
    • Alvarez-Diaz S 4
    • Herold MJ 4
    • Masters SL 1, 4
    (6 authors)

ORCIDs linked to this article

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European Journal of Immunology, 24 Aug 2015, 45(10):2918-2926
https://doi.org/10.1002/eji.201545655 PMID: 26173988 

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.

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Read article at publisher's site: https://doi.org/10.1002/eji.201545655

Read article for free, from open access legal sources, via Unpaywall: https://onlinelibrary.wiley.com/doi/pdfdirect/10.1002/eji.201545655Unpaywall

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Funding 

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National Health and Medical Research Council (1)