The non-canonical inflammasome sensor caspase-11 and gasdermin D (GSDMD) drive inflammation and py-roptosis, 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 in-ducers 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 ad-juvants. 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.
Non-canonical inflammasome activation mediates the adjuvanticity of nanoparticles / N. Muñoz-Wolf, R.W. Ward, C.H. Hearnden, F.A. Sharp, J. Geoghegan, K. O'Grady, C.P. Mcentee, K.A. Shanahan, C. Guy, A.G. Bowie, M. Campbell, C.B. Roces, G. Anderluzzi, C. Webb, Y. Perrie, E. Creagh, E.C. Lavelle. - In: CELL REPORTS MEDICINE. - ISSN 2666-3791. - 4:1(2023 Jan 17), pp. 100899.1-100899.22. [10.1016/j.xcrm.2022.100899]
Non-canonical inflammasome activation mediates the adjuvanticity of nanoparticles
G. Anderluzzi;
2023
Abstract
The non-canonical inflammasome sensor caspase-11 and gasdermin D (GSDMD) drive inflammation and py-roptosis, 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 in-ducers 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 ad-juvants. 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.File | Dimensione | Formato | |
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