Non-canonical inflammasome activation mediates the adjuvanticity of nanoparticles

Muñoz-Wolf, Natalia and Ward, Ross W. and Hearnden, Claire H. and Sharp, Fiona A. and Geoghegan, Joan and O'Grady, Katie and McEntee, Craig P. and Shanahan, Katharine A. and Guy, Coralie and Bowie, Andrew G. and Campbell, Matthew and Roces, Carla B. and Anderluzzi, Giulia and Webb, Cameron and Perrie, Yvonne and Creagh, Emma and Lavelle, Ed C. (2023) Non-canonical inflammasome activation mediates the adjuvanticity of nanoparticles. Cell Reports Medicine, 4 (1). 100899. (https://doi.org/10.1016/j.xcrm.2022.100899)

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Abstract

The non-canonical inflammasome sensor caspase-11 and gasdermin D (GSDMD) drive inflammation and pyroptosis, a type of immunogenic cell death that favors cell-mediated immunity (CMI) in cancer, infection, and autoimmunity. Here we show that caspase-11 and GSDMD are required for CD8+ and Th1 responses induced by nanoparticulate vaccine adjuvants. We demonstrate that nanoparticle-induced reactive oxygen species (ROS) are size dependent and essential for CMI, and we identify 50- to 60-nm nanoparticles as optimal inducers of ROS, GSDMD activation, and Th1 and CD8+ responses. We reveal a division of labor for IL-1 and IL-18, where IL-1 supports Th1 and IL-18 promotes CD8+ responses. Exploiting size as a key attribute, we demonstrate that biodegradable poly-lactic co-glycolic acid nanoparticles are potent CMI-inducing adjuvants. Our work implicates ROS and the non-canonical inflammasome in the mode of action of polymeric nanoparticulate adjuvants and establishes adjuvant size as a key design principle for vaccines against cancer and intracellular pathogens.

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