Identification of QS-21 as an Inflammasome-activating Molecular Component of Saponin Adjuvants.

Abstract

Many immunostimulants act as vaccine adjuvants via activation of the innate immune system, although in many cases it is unclear which specific molecules contribute to the stimulatory activity. QS-21 is a defined, highly purified, and soluble saponin adjuvant currently used in licensed and exploratory vaccines, including vaccines against malaria, cancer, and HIV-1. However, little is known about the mechanisms of cellular activation induced by QS-21. We observed QS-21 to elicit caspase-1-dependent IL-1β and IL-18 release in antigen-presenting cells such as macrophages and dendritic cells when co-stimulated with the TLR4-agonist adjuvant monophosphoryl lipid A. Furthermore, our data suggest that the ASC-NLRP3 inflammasome is responsible for QS-21-induced IL-1β/IL-18 release. At higher concentrations, QS-21 induced macrophage and dendritic cell death in a caspase-1-, ASC-, and NLRP3-independent manner, whereas the presence of cholesterol rescued cell viability. A nanoparticulate adjuvant that contains QS-21 as part of a heterogeneous mixture of saponins also induced IL-1β in an NLRP3-dependent manner. Interestingly, despite the role NLRP3 plays for cellular activation in vitro, NLRP3-deficient mice immunized with HIV-1 gp120 and QS-21 showed significantly higher levels of Th1 and Th2 antigen-specific T cell responses and increased IgG1 and IgG2c compared with wild type controls. Thus, we have identified QS-21 as a nonparticulate single molecular saponin that activates the NLRP3 inflammasome, but this signaling pathway may contribute to decreased antigen-specific responses in vivo.

• Authors: Robyn Marty-Roix, Gregory I Vladimer, Kimberly Pouliot, Dan Weng, Rachel Buglione-Corbett, Kim West, John D MacMicking, Jonathan D Chee, Shixia Wang, Shan Lu, Egil Lien
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 291 Issue 3 Pg. 1123-36 (Jan 15 2016) ISSN: 1083-351X [Electronic] United States
• PMID: 26555265 (Publication Type: Journal Article, Research Support, American Recovery and Reinvestment Act, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

Chemical References

• AIDS Vaccines
• Adjuvants, Immunologic
• Carrier Proteins
• HIV Envelope Protein gp120
• HIV-1 IIIB gp120 subunit vaccine
• Immunoglobulin G
• Inflammasomes
• Lipid A
• NLR Family, Pyrin Domain-Containing 3 Protein
• Nlrp3 protein, mouse
• Saponins
• saponin QA-21V1
• GTP-Binding Proteins
• Gbp5 protein, mouse
• monophosphoryl lipid A

Topics

• AIDS Vaccines (agonists, immunology)
• Adjuvants, Immunologic (analysis, chemistry, pharmacology)
• Animals
• Bone Marrow Cells (cytology, drug effects, immunology)
• Carrier Proteins (genetics, metabolism)
• Cell Survival (drug effects)
• Cells, Cultured
• Dendritic Cells (cytology, drug effects, immunology)
• GTP-Binding Proteins (genetics, metabolism)
• HIV Envelope Protein gp120 (agonists, immunology)
• Immunity, Innate (drug effects)
• Immunoglobulin G (analysis, biosynthesis)
• Inflammasomes (drug effects, immunology, metabolism)
• Lipid A (agonists, analogs & derivatives, pharmacology)
• Macrophages (cytology, drug effects, immunology)
• Mice, Inbred C57BL
• Mice, Knockout
• NLR Family, Pyrin Domain-Containing 3 Protein
• Saponins (analysis, chemistry, pharmacology)
• Solubility
• Th1 Cells (drug effects, immunology, metabolism)
• Th2 Cells (drug effects, immunology, metabolism)