Cutting Edge: Inflammasome Activation by Alum and Alum’s Adjuvant Effect Are Mediated by NLRP3

TLDR

Alum is the only routinely approved human adjuvant, yet its mechanism of action is poorly understood, and other particulate adjuvants such as QuilA and chitosan also activate the NLRP3 inflammasome, implying a common pathway. The study aims to determine whether alum‑induced cytokine secretion in macrophages is mediated by the NLRP3 inflammasome and its adaptor ASC. The authors used human and mouse macrophages to demonstrate that alum triggers IL‑1β, IL‑18, and IL‑33 secretion through the NLRP3 inflammasome and ASC, but not via NLRC4. The study shows that alum activates caspase‑1 and induces IL‑1β, IL‑18, and IL‑33 secretion via NLRP3, that NLRP3 deficiency markedly reduces alum‑driven antibody responses, and that targeting NLRP3 could enhance vaccine adjuvant efficacy.

Abstract

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-1β and IL-18. In this study we show that, in human and mouse macrophages, alum-induced secretion of IL-1β, 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.