Cutting edge: inflammasome activation by alum and alum's adjuvant effect are mediated by NLRP3

J Immunol. 2008 Jul 1;181(1):17-21. doi: 10.4049/jimmunol.181.1.17.

Abstract

Alum is the only adjuvant approved for routine use in humans, although the basis for its adjuvanticity remains poorly understood. We have recently shown that alum activates caspase-1 and induces secretion of mature IL-1beta and IL-18. In this study we show that, in human and mouse macrophages, alum-induced secretion of IL-1beta, IL-18, and IL-33 is mediated by the NLR (nucleotide-binding domain leucine-rich repeat-containing) protein NLRP3 and its adaptor ASC, but not by NLRC4. Other particulate adjuvants, such as QuilA and chitosan, induce inflammasome activation in a NLRP3-dependent fashion, suggesting that activation of the NLRP3-inflammasome may be a common mechanism of action of particulate adjuvants. Importantly, we demonstrate that Ag-specific Ab production elicited by vaccines that contain alum is significantly impaired in NLRP3-deficient mice. Our results demonstrate for the first time a role for the NLRP3-inflammasome during development of the immune response elicited by alum-enhanced vaccination and suggest that therapeutic intervention aimed at NLRP3 may improve adjuvant efficacy.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adjuvants, Immunologic / pharmacology*
  • Aluminum Compounds / pharmacology*
  • Aluminum Hydroxide / pharmacology*
  • Animals
  • Carrier Proteins / genetics
  • Carrier Proteins / immunology*
  • Carrier Proteins / metabolism*
  • Cell Line
  • Cells, Cultured
  • Humans
  • Immune System / drug effects
  • Immune System / immunology
  • Inflammation / immunology
  • Mice
  • Mice, Knockout
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • Phosphates / pharmacology*
  • RNA Interference

Substances

  • Adjuvants, Immunologic
  • Aluminum Compounds
  • Carrier Proteins
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • Nlrp3 protein, mouse
  • Phosphates
  • Aluminum Hydroxide
  • aluminum phosphate