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

TY - JOUR

T1 - NLRP3 inflammasome activation downstream of cytoplasmic LPS recognition by both caspase-4 and caspase-5

AU - Baker, Paul J

AU - Boucher, Dave

AU - Bierschenk, Damien

AU - Tebartz, Christina

AU - Whitney, Paul G

AU - D'Silva, Damian B

AU - Tanzer, Maria C

AU - Monteleone, Mercedes

AU - Robertson, Avril A B

AU - Cooper, Matthew A

AU - Alvarez-Diaz, Silvia

AU - Herold, Marco J

AU - Bedoui, Sammy

AU - Schroder, Kate

AU - Masters, Seth L

N1 - © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

PY - 2015/10/6

Y1 - 2015/10/6

N2 - 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.

AB - 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.

KW - Carrier Proteins/immunology

KW - Caspases/immunology

KW - Caspases, Initiator/immunology

KW - Cell Line, Tumor

KW - Humans

KW - Interleukin-1beta/immunology

KW - Lipopolysaccharides/immunology

KW - Monocytes/immunology

KW - NLR Family, Pyrin Domain-Containing 3 Protein

KW - Salmonella Infections/immunology

KW - Salmonella typhimurium/immunology

U2 - 10.1002/eji.201545655

DO - 10.1002/eji.201545655

M3 - Article

C2 - 26173988

SN - 0014-2980

VL - 45

SP - 2918

EP - 2926

JO - European Journal of Immunology

JF - European Journal of Immunology

IS - 10

ER -