title: Uptake of particulate vaccine adjuvants by dendritic cells activates the NALP3 inflammasome.
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.
authors.affiliation: Adjuvant Research Group, School of Biochemistry and Immunology, Trinity College, Dublin 2, Ireland.
authors.forename: Fiona A
authors.initials: FA
authors.lastname: Sharp
authors.forename: Darren
authors.initials: D
authors.lastname: Ruane
authors.forename: Benjamin
authors.initials: B
authors.lastname: Claass
authors.forename: Emma
authors.initials: E
authors.lastname: Creagh
authors.forename: James
authors.initials: J
authors.lastname: Harris
authors.forename: Padma
authors.initials: P
authors.lastname: Malyala
authors.forename: Manomohan
authors.initials: M
authors.lastname: Singh
authors.forename: Derek T
authors.initials: DT
authors.lastname: O'Hagan
authors.forename: Virginie
authors.initials: V
authors.lastname: Pétrilli
authors.forename: Jurg
authors.initials: J
authors.lastname: Tschopp
authors.forename: Luke A J
authors.initials: LA
authors.lastname: O'Neill
authors.forename: Ed C
authors.initials: EC
authors.lastname: Lavelle
mesh_terms: D000276:Adjuvants, Immunologic / Q000493:pharmacokinetics / Q000494:pharmacology*; D000818:Animals; D000917:Antibody Formation; D002352:Carrier Proteins / Q000502:physiology*; D020170:Caspase 1 / Q000502:physiology; D002401:Cathepsin B / Q000502:physiology; D002465:Cell Movement; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000378:metabolism*; D005260:Female; D053583:Interleukin-1beta / Q000096:biosynthesis; D019344:Lactic Acid / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D011100:Polyglycolic Acid / Q000494:pharmacology; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011137:Polystyrenes / Q000494:pharmacology; D051193:Toll-Like Receptors / Q000502:physiology; D014612:Vaccines / Q000008:administration & dosage*
chemical_list: D000276:Adjuvants, Immunologic; D002352:Carrier Proteins; D053583:Interleukin-1beta; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse; D011137:Polystyrenes; D051193:Toll-Like Receptors; D014612:Vaccines; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D019344:Lactic Acid; D002401:Cathepsin B; D020170:Caspase 1