Uptake of particulate vaccine adjuvants by dendritic cells activates the NALP3 inflammasome.
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Uptake of particulate vaccine adjuvants by dendritic cells activates the NALP3 inflammasome. / Sharp, Fiona A; Ruane, Darren; Claaß, Benjamin; Creagh, Emma; Harris, James; Malyala, Padma; Singh, Manomohan; O'Hagan, Derek T; Pétrilli, Virginie; Tschopp, Jurg; O'Neill, Luke A J; Lavelle, Ed C.
in: P NATL ACAD SCI USA, Jahrgang 106, Nr. 3, 3, 2009, S. 870-875.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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T1 - Uptake of particulate vaccine adjuvants by dendritic cells activates the NALP3 inflammasome.
AU - Sharp, Fiona A
AU - Ruane, Darren
AU - Claaß, Benjamin
AU - Creagh, Emma
AU - Harris, James
AU - Malyala, Padma
AU - Singh, Manomohan
AU - O'Hagan, Derek T
AU - Pétrilli, Virginie
AU - Tschopp, Jurg
AU - O'Neill, Luke A J
AU - Lavelle, Ed C
PY - 2009
Y1 - 2009
N2 - 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.
AB - 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.
KW - Animals
KW - Female
KW - Cells, Cultured
KW - Mice
KW - Mice, Inbred C57BL
KW - Cell Movement
KW - Antibody Formation
KW - Lactic Acid/pharmacology
KW - Adjuvants, Immunologic/pharmacokinetics/pharmacology
KW - Carrier Proteins/physiology
KW - Caspase 1/physiology
KW - Cathepsin B/physiology
KW - Dendritic Cells/metabolism
KW - Interleukin-1beta/biosynthesis
KW - Polyglycolic Acid/pharmacology
KW - Polystyrenes/pharmacology
KW - Toll-Like Receptors/physiology
KW - Vaccines/administration & dosage
KW - Animals
KW - Female
KW - Cells, Cultured
KW - Mice
KW - Mice, Inbred C57BL
KW - Cell Movement
KW - Antibody Formation
KW - Lactic Acid/pharmacology
KW - Adjuvants, Immunologic/pharmacokinetics/pharmacology
KW - Carrier Proteins/physiology
KW - Caspase 1/physiology
KW - Cathepsin B/physiology
KW - Dendritic Cells/metabolism
KW - Interleukin-1beta/biosynthesis
KW - Polyglycolic Acid/pharmacology
KW - Polystyrenes/pharmacology
KW - Toll-Like Receptors/physiology
KW - Vaccines/administration & dosage
M3 - SCORING: Journal article
VL - 106
SP - 870
EP - 875
JO - P NATL ACAD SCI USA
JF - P NATL ACAD SCI USA
SN - 0027-8424
IS - 3
M1 - 3
ER -
