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Eur J Immunol. 2015 Oct;45(10):2918-26. doi: 10.1002/eji.201545655. Epub 2015 Aug 24.

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

Author information

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.

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

PMID:
26173988
DOI:
10.1002/eji.201545655
[Indexed for MEDLINE]
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