Journal article

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

Paul J Baker, Dave Boucher, Damien Bierschenk, Christina Tebartz, Paul G Whitney, Damian B D'Silva, Maria C Tanzer, Mercedes Monteleone, Avril AB Robertson, Matthew A Cooper, Silvia Alvarez-Diaz, Marco J Herold, Sammy Bedoui, Kate Schroder, Seth L Masters



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 casp..

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Awarded by National Health and Medical Research Council of Australia

Awarded by Australian Research Council Future Fellowship

Funding Acknowledgements

We would like to thank Dr. J. E. Vince, Dr. K. E. Lawlor, and Dr. K. Schaale for supplying reagents and technical advice. This work was supported by the National Health and Medical Research Council of Australia Project Grants (APP1057815 to S.L.M. and APP1064945 to K.S.) and a Career Development Fellowship to S.L.M. K.S. is supported by an Australian Research Council Future Fellowship (FT130100361), and the Queensland Smart Futures Fund. D.B. is a Fellow from the Fonds de Recherche du Quebec en Sante and C.T. was supported by a fellowship from the Deutsche Forschungsgemeinschaft. P.J.B. holds an Australian Postgraduate Award, D.B. holds an International Postgraduate Research Scholarship and the UQ Centennial Scholarship, and M.C.T. holds a Victorian International Research Scholarship.