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

Baker, Paul J., Boucher, Dave, Bierschenk, Damien, Tebartz, Christina, Whitney, Paul G., D'Silva, Damian B, Tanzer, Marco J., Monteleone, Mercedes, Robertson, Avril A.B., Cooper, Matthew A., Alvarez-Diaz, Silvia, Herold, Marco J., Bedoui, Sammy, Schroder, Kate and Masters, Seth L. (2015) NLRP3 inflammasome activation downstream of cytoplasmic LPS recognition by both caspase-4 and caspase-5. European Journal of Immunology, 45 10: 2918-2926. doi:10.1002/eji.201545655


Author Baker, Paul J.
Boucher, Dave
Bierschenk, Damien
Tebartz, Christina
Whitney, Paul G.
D'Silva, Damian B
Tanzer, Marco J.
Monteleone, Mercedes
Robertson, Avril A.B.
Cooper, Matthew A.
Alvarez-Diaz, Silvia
Herold, Marco J.
Bedoui, Sammy
Schroder, Kate
Masters, Seth L.
Title NLRP3 inflammasome activation downstream of cytoplasmic LPS recognition by both caspase-4 and caspase-5
Journal name European Journal of Immunology   Check publisher's open access policy
ISSN 1521-4141
0014-2980
Publication date 2015-10-01
Year available 2015
Sub-type Article (original research)
DOI 10.1002/eji.201545655
Open Access Status Not Open Access
Volume 45
Issue 10
Start page 2918
End page 2926
Total pages 9
Place of publication Weinheim, Germany
Publisher Wiley-VCH Verlag
Collection year 2016
Language eng
Formatted 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.
Keyword Caspase-4
Caspase-5
LPS
NLRP3 inflammasome
Pyroptosis
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2016 Collection
Institute for Molecular Bioscience - Publications
 
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