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. 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

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
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Free article

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

Paul J Baker et al. Eur J Immunol. 2015 Oct.
Free article

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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