Squalene emulsion potentiates the adjuvant activity of the TLR4 agonist, GLA, via inflammatory caspases, IL-18, and IFN-γ

Eur J Immunol. 2015 Feb;45(2):407-17. doi: 10.1002/eji.201444543. Epub 2014 Dec 3.

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.

Keywords: Adjuvants; Innate immunity; Squalene; TLR4; Th1 immunity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptive Immunity / drug effects
  • Adjuvants, Immunologic / administration & dosage*
  • Adjuvants, Immunologic / chemical synthesis
  • Animals
  • CD8-Positive T-Lymphocytes / cytology
  • CD8-Positive T-Lymphocytes / drug effects
  • CD8-Positive T-Lymphocytes / immunology
  • Caspase 1 / genetics
  • Caspase 1 / immunology*
  • Caspases / genetics
  • Caspases / immunology*
  • Caspases, Initiator
  • Emulsions
  • Female
  • Gene Expression
  • Immunity, Innate / drug effects
  • Immunization
  • Immunologic Memory
  • Inflammasomes / drug effects
  • Interferon-gamma / biosynthesis
  • Interferon-gamma / immunology*
  • Interleukin-18 / biosynthesis
  • Interleukin-18 / immunology*
  • Lipids / administration & dosage
  • Lipids / chemical synthesis
  • Lipids / immunology
  • Mice
  • Mice, Knockout
  • Neutrophils / cytology
  • Neutrophils / drug effects
  • Neutrophils / immunology
  • Receptors, Interleukin-18 / genetics
  • Receptors, Interleukin-18 / immunology
  • Squalene / administration & dosage*
  • Squalene / chemistry
  • Squalene / immunology
  • Th1 Cells / cytology
  • Th1 Cells / drug effects
  • Th1 Cells / immunology
  • Toll-Like Receptor 4 / agonists*
  • Toll-Like Receptor 4 / genetics
  • Toll-Like Receptor 4 / immunology

Substances

  • Adjuvants, Immunologic
  • Emulsions
  • Inflammasomes
  • Interleukin-18
  • Lipids
  • Receptors, Interleukin-18
  • Tlr4 protein, mouse
  • Toll-Like Receptor 4
  • Squalene
  • Interferon-gamma
  • Casp4 protein, mouse
  • Caspases
  • Caspases, Initiator
  • Caspase 1