NLRP3 inflammasome activation downstream of cytoplasmic LPS recognition by both caspase‐4 and caspase‐5 |
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| Authors: | Paul J Baker Dave Boucher Damien Bierschenk Christina Tebartz Paul G Whitney Damian B D'Silva Maria C Tanzer Mercedes Monteleone Avril A B Robertson Matthew A Cooper Silvia Alvarez‐Diaz Marco J Herold Sammy Bedoui Kate Schroder Seth L Masters |
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| Institution: | 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 |
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| 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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| Keywords: | Caspase‐4 Caspase‐5 LPS NLRP3 inflammasome Pyroptosis |
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