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Cutting Edge: Inflammasome Activation by Alum and Alum’s Adjuvant Effect Are Mediated by NLRP3¹

Hanfen Li^*, Stephen B. Willingham, Jenny P.-Y. Ting and Fabio Re^2,*

^* Department Molecular Sciences, University of Tennessee Health Science Center, Memphis, TN 38163; and Lineberger Comprehensive Cancer Center, Curriculum in Genetics and Molecular Biology, Department of Microbiology and Immunology, University of North Carolina, Chapel Hill, NC 27599

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.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by National Institutes of Health Grants R21AI076835-01 (to F.R.) and R01AI057157, R01AI063031, R01DE16326, and SERCEB A1-02-031 (to J.P.-Y.T.).

² Address correspondence and reprint requests to Dr. Fabio Re, Department Molecular Sciences, University of Tennessee Health Science Center, 858 Madison Avenue, Memphis, TN 38163. E-mail address: fre{at}utmem.edu

³ Abbreviations used in this paper: DC, dendritic cell; BMM, bone marrow-derived mononuclear cell; DT, diphtheria toxoid; Lf, flocculation unit; NLR, nucleotide-binding domain leucine-rich repeat-containing (protein/family); shRNA, short hairpin RNA; TT, tetanus toxoid; Z-YVAD-FMK, N-benzyloxycarbonyl-Tyr-Val-Ala-Asp-fluoromethyl ketone.