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Depression: 21st Century Solutions + The Dark Side of Wheat

Abstract Title:

Uptake of particulate vaccine adjuvants by dendritic cells activates the NALP3 inflammasome.

Abstract Source:

Proc Natl Acad Sci U S A. 2009 Jan 20 ;106(3):870-5. Epub 2009 Jan 12. PMID: 19139407

Abstract Author(s):

Fiona A Sharp, Darren Ruane, Benjamin Claass, Emma Creagh, James Harris, Padma Malyala, Manomohan Singh, Derek T O'Hagan, Virginie Pétrilli, Jurg Tschopp, Luke A J O'Neill, Ed C Lavelle

Article Affiliation:

Adjuvant Research Group, School of Biochemistry and Immunology, Trinity College, Dublin 2, Ireland.

Abstract:

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-1beta (IL-1beta) by dendritic cells (DCs). The ability of particulates to promote IL-1beta secretion and caspase 1 activation required particle uptake by DCs and NALP3. Uptake of microparticles induced lysosomal damage, whereas particle-mediated enhancement of IL-1beta 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-1beta production in vitro, injection of the adjuvants in the absence of TLR agonists induced IL-1beta 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.

Study Type : In Vitro Study

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Sayer Ji
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Depression: 21st Century Solutions + The Dark Side of Wheat

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