title: Squalene emulsion potentiates the adjuvant activity of the TLR4 agonist, GLA, via inflammatory caspases, IL-18, and IFN-γ.
abstract: The synthetic TLR4 agonist glucopyranosyl lipid adjuvant (GLA) is a potent Th1-response-inducing adjuvant when formulated in a squalene oil-in-water emulsion (SE). While the innate signals triggered by TLR4 engagement are well studied, the contribution of SE remains unclear. To better understand the effect of SE on the adjuvant properties of GLA-SE, we compared the innate and adaptive immune responses elicited by immunization with different formulations: GLA without oil, SE alone or the combination, GLA-SE, in mice. Within the innate response to adjuvants, only GLA-SE displayed features of inflammasome activation, evidenced by early IL-18 secretion and IFN-γ production in memory CD8(+) T cells and neutrophils. Such early IFN-γ production was ablated in caspase-1/11(-/-) mice and in IL-18R1(-/-) mice. Furthermore, caspase-1/11 and IL-18 were also required for full Th1 CD4(+) T-cell induction via GLA-SE. Thus, we demonstrate that IL-18 and caspase-1/11 are components of the response to immunization with the TLR4 agonist/squalene oil-in-water based adjuvant, GLA-SE, providing implications for other adjuvants that combine oils with TLR agonists.
authors.affiliation: Infectious Disease Research Institute, Seattle, WA, USA.
authors.forename: Anthony L
authors.initials: AL
authors.lastname: Desbien
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Reed
authors.forename: Hilton R
authors.initials: HR
authors.lastname: Bailor
authors.forename: Natasha
authors.initials: N
authors.lastname: Dubois Cauwelaert
authors.forename: John D
authors.initials: JD
authors.lastname: Laurance
authors.forename: Mark T
authors.initials: MT
authors.lastname: Orr
authors.forename: Christopher B
authors.initials: CB
authors.lastname: Fox
authors.forename: Darrick
authors.initials: D
authors.lastname: Carter
authors.forename: Steven G
authors.initials: SG
authors.lastname: Reed
authors.forename: Malcolm S
authors.initials: MS
authors.lastname: Duthie
mesh_terms: D056704:Adaptive Immunity / Q000187:drug effects; D000276:Adjuvants, Immunologic / Q000008:administration & dosage* / Q000138:chemical synthesis; D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D020170:Caspase 1 / Q000235:genetics / Q000276:immunology*; D020169:Caspases / Q000235:genetics / Q000276:immunology*; D053471:Caspases, Initiator; D004655:Emulsions; D005260:Female; D015870:Gene Expression; D007113:Immunity, Innate / Q000187:drug effects; D007114:Immunization; D007156:Immunologic Memory; D058847:Inflammasomes / Q000187:drug effects; D007371:Interferon-gamma / Q000096:biosynthesis / Q000276:immunology*; D020382:Interleukin-18 / Q000096:biosynthesis / Q000276:immunology*; D008055:Lipids / Q000008:administration & dosage / Q000138:chemical synthesis / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D009504:Neutrophils / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D053724:Receptors, Interleukin-18 / Q000235:genetics / Q000276:immunology; D013185:Squalene / Q000008:administration & dosage* / Q000737:chemistry / Q000276:immunology; D018417:Th1 Cells / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D051197:Toll-Like Receptor 4 / Q000819:agonists* / Q000235:genetics / Q000276:immunology
chemical_list: D000276:Adjuvants, Immunologic; D004655:Emulsions; D058847:Inflammasomes; D020382:Interleukin-18; D008055:Lipids; D053724:Receptors, Interleukin-18; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D013185:Squalene; D007371:Interferon-gamma; C101136:Casp4 protein, mouse; D020169:Caspases; D053471:Caspases, Initiator; D020170:Caspase 1
keywords: Adjuvants; Innate immunity; Squalene; TLR4; Th1 immunity