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

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

Research output: Contribution to journalArticleResearchpeer-review

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.
Original languageEnglish
Pages (from-to)870 - 875
Number of pages6
JournalProceedings of the National Academy of Sciences
Volume106
Issue number3
DOIs
Publication statusPublished - 2009

Cite this

Sharp, Fiona A ; Ruane, Darren Thomas ; Claass, Benjamin ; Creagh, Emma ; Harris, James ; Malyala, Padma ; Singh, Manomohan ; O'Hagan, Derek T ; Petrilli, Virginie ; Tschopp, Jurg ; O'Neill, Luke A J ; Lavelle, Ed C. / Uptake of particulate vaccine adjuvants by dendritic cells activates the NALP3 inflammasome. In: Proceedings of the National Academy of Sciences. 2009 ; Vol. 106, No. 3. pp. 870 - 875.
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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.",
author = "Sharp, {Fiona A} and Ruane, {Darren Thomas} and Benjamin Claass and Emma Creagh and James Harris and Padma Malyala and Manomohan Singh and O'Hagan, {Derek T} and Virginie Petrilli and Jurg Tschopp and O'Neill, {Luke A J} and Lavelle, {Ed C}",
year = "2009",
doi = "10.1073/pnas.0804897106",
language = "English",
volume = "106",
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journal = "Proceedings of the National Academy of Sciences of the United States of America",
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Sharp, FA, Ruane, DT, Claass, B, Creagh, E, Harris, J, Malyala, P, Singh, M, O'Hagan, DT, Petrilli, V, Tschopp, J, O'Neill, LAJ & Lavelle, EC 2009, 'Uptake of particulate vaccine adjuvants by dendritic cells activates the NALP3 inflammasome' Proceedings of the National Academy of Sciences, vol. 106, no. 3, pp. 870 - 875. https://doi.org/10.1073/pnas.0804897106

Uptake of particulate vaccine adjuvants by dendritic cells activates the NALP3 inflammasome. / Sharp, Fiona A; Ruane, Darren Thomas; Claass, Benjamin; Creagh, Emma; Harris, James; Malyala, Padma; Singh, Manomohan; O'Hagan, Derek T; Petrilli, Virginie; Tschopp, Jurg; O'Neill, Luke A J; Lavelle, Ed C.

In: Proceedings of the National Academy of Sciences, Vol. 106, No. 3, 2009, p. 870 - 875.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Uptake of particulate vaccine adjuvants by dendritic cells activates the NALP3 inflammasome

AU - Sharp, Fiona A

AU - Ruane, Darren Thomas

AU - Claass, Benjamin

AU - Creagh, Emma

AU - Harris, James

AU - Malyala, Padma

AU - Singh, Manomohan

AU - O'Hagan, Derek T

AU - Petrilli, 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.

UR - http://www.ncbi.nlm.nih.gov/pubmed/19139407

U2 - 10.1073/pnas.0804897106

DO - 10.1073/pnas.0804897106

M3 - Article

VL - 106

SP - 870

EP - 875

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

SN - 0027-8424

IS - 3

ER -