title: Activation of the NLRP3 inflammasome is not a feature of all particulate vaccine adjuvants.
abstract: Particulate vaccine formulations, designed to improve the delivery of antigens to antigen-presenting cells (APCs) and to stimulate an immune response, have been shown to activate the NLRP3 inflammasome. This leads to the processing and secretion of interleukin (IL)-1β, which supports the recruitment of pro-inflammatory immune cells into the tissue and can therefore be beneficial for vaccine potency. Recent work suggested that this may be a common mechanism of action for all particulate formulations. The aim of this study was to investigate whether the activation of the NLRP3 inflammasome was common to many delivery systems. We prepared polymer-based chitosan nanoparticles (CNPs), lipid-based cubosomes, a water in oil emulsion of incomplete Freund's adjuvant (IFA) and alum formulations and examined inflammasome activation in vitro using murine bone-marrow-derived dendritic cells and human peripheral blood mononuclear cells and in vivo in mice. The formulations differed in their morphology, size and zeta-potential. Only the positively charged particles (CNPs and alum) were able to activate the inflammasome and increase the secretion of IL-1β. A decrease in the activation of the inflammasome with these particulates was observed when cathepsin B-mediated effects were blocked, implying a role of lysosomal rupture in the activation process. These findings demonstrate a role for the surface charge of particulates in the activation of the NLRP3 inflammasome, which should be considered when designing a novel vaccine formulation.
authors.affiliation: 1] School of Pharmacy, University of Otago, Dunedin, New Zealand [2] Maurice Wilkins Centre for Molecular Biodiscovery, University of Auckland, Auckland, New Zealand.
authors.forename: Silke
authors.initials: S
authors.lastname: Neumann
authors.affiliation: 1] Maurice Wilkins Centre for Molecular Biodiscovery, University of Auckland, Auckland, New Zealand [2] School of Biological Sciences, University of Auckland, Auckland, New Zealand.
authors.forename: Kristina
authors.initials: K
authors.lastname: Burkert
authors.affiliation: Department of Microbiology and Immunology, University of Otago, Dunedin, New Zealand.
authors.forename: Roslyn
authors.initials: R
authors.lastname: Kemp
authors.affiliation: Department of Pharmacy, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Thomas
authors.initials: T
authors.lastname: Rades
authors.affiliation: 1] Maurice Wilkins Centre for Molecular Biodiscovery, University of Auckland, Auckland, New Zealand [2] School of Biological Sciences, University of Auckland, Auckland, New Zealand.
authors.forename: P
authors.initials: P
authors.lastname: Rod Dunbar
authors.affiliation: 1] School of Pharmacy, University of Otago, Dunedin, New Zealand [2] Maurice Wilkins Centre for Molecular Biodiscovery, University of Auckland, Auckland, New Zealand.
authors.forename: Sarah
authors.initials: S
authors.lastname: Hook
mesh_terms: D000276:Adjuvants, Immunologic / Q000494:pharmacology*; D000534:Alum Compounds / Q000494:pharmacology; D000818:Animals; D002352:Carrier Proteins / Q000276:immunology*; D002401:Cathepsin B / Q000276:immunology; D048271:Chitosan / Q000494:pharmacology; D005260:Female; D005620:Freund's Adjuvant / Q000494:pharmacology; D006801:Humans; D058847:Inflammasomes / Q000276:immunology*; D053583:Interleukin-1beta / Q000276:immunology; D008297:Male; D051379:Mice; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D053758:Nanoparticles
chemical_list: D000276:Adjuvants, Immunologic; D000534:Alum Compounds; D002352:Carrier Proteins; C508585:IL1B protein, human; C587672:IL1B protein, mouse; D058847:Inflammasomes; D053583:Interleukin-1beta; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C453881:NLRP3 protein, human; C492716:Nlrp3 protein, mouse; C041524:aluminum sulfate; D005620:Freund's Adjuvant; D048271:Chitosan; C533912:CTSB protein, human; D002401:Cathepsin B; C533915:Ctsb protein, mouse