Uptake of particulate vaccine adjuvants by dendritic cells activates the NALP3 inflammasome.
Item Type:Journal Article
Citation:Sharp, F., Ruane, D., Claas, B., Creagh, E., Harris, J., Malyala, P., Singh, M., O'Hagan, D.T., P?trilli, V., Tschopp, J., O'Neill, L.A.J. and *Lavelle, E.C, Uptake of particulate vaccine adjuvants by dendritic cells activates the NALP3 inflammasome., Proceedings of the National Academy of Sciences of the U.S.A, 106, 3, 2009, 870-875
Uptake of particulate vaccine adjuvants by dendritic cells activates the NALP3 inflammasome.pdf (published (publisher copy) peer-reviewed) 777.6Kb
Many currently used and candidate vaccine adjuvants are particulate in nature, but their mechanism of action is not well understood. Here, we show that particulate adjuvants, including biodegradable poly(lactide-co-glycolide) (PLG) and polystyrene microparticles, dramatically enhance secretion of interleukin-1? (IL-1?) by dendritic cells (DCs). The ability of particulates to promote IL-1? secretion and caspase 1 activation required particle uptake by DCs and NALP3. Uptake of microparticles induced lysosomal damage, whereas particle-mediated enhancement of IL-1? secretion required phagosomal acidification and the lysosomal cysteine protease cathepsin B, suggesting a role for lysosomal damage in inflammasome activation. Although the presence of a Toll-like receptor (TLR) agonist was required to induce IL-1? production in vitro, injection of the adjuvants in the absence of TLR agonists induced IL-1? production at the injection site, indicating that endogenous factors can synergize with particulates to promote inflammasome activation. The enhancement of antigen-specific antibody production by PLG microparticles was independent of NALP3. However, the ability of PLG microparticles to promote antigen-specific IL-6 production by T cells and the recruitment and activation of a population of CD11b+Gr1? cells required NALP3. Our data demonstrate that uptake of microparticulate adjuvants by DCs activates the NALP3 inflammasome, and this contributes to their enhancing effects on innate and antigen-specific cellular immunity.
Type of material:Journal Article
Series/Report no:Proceedings of the National Academy of Sciences of the U.S.A
Availability:Full text available
Keywords:Caspase-1 IL-1 microparticle