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

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.

[1]  A. Khoruts,et al.  Inflammatory cytokines enhance the in vivo clonal expansion and differentiation of antigen-activated CD4+ T cells. , 1997, Journal of immunology.

[2]  A. H. Coons,et al.  STUDIES ON ANTIBODY PRODUCTION VIII. THE INHIBITORY EFFECT OF CHLORAMPHENICOL ON THE SYNTHESIS OF ANTIBODY IN TISSUE CULTURE , 1963 .

[3]  Alan Aderem,et al.  Cytoplasmic flagellin activates caspase-1 and secretion of interleukin 1β via Ipaf , 2006, Nature Immunology.

[4]  H. Iocca,et al.  Cutting Edge: ASC Mediates the Induction of Multiple Cytokines by Porphyromonas gingivalis via Caspase-1-Dependent and -Independent Pathways1 , 2006, The Journal of Immunology.

[5]  R. White,et al.  Studies on antibody production. III. The alum granuloma. , 1955 .

[6]  Henk C. Hoogsteden,et al.  Alum adjuvant boosts adaptive immunity by inducing uric acid and activating inflammatory dendritic cells , 2008, The Journal of experimental medicine.

[7]  J. Bertin,et al.  Cytosolic flagellin requires Ipaf for activation of caspase-1 and interleukin 1β in salmonella-infected macrophages , 2006, Nature Immunology.

[8]  Vasso Apostolopoulos,et al.  Pathogen recognition and development of particulate vaccines: does size matter? , 2006, Methods.

[9]  Hongfan Sun,et al.  Analysis of the role of vaccine adjuvants in modulating dendritic cell activation and antigen presentation in vitro. , 2003, Vaccine.

[10]  B. Beutler,et al.  Adjuvant-Enhanced Antibody Responses in the Absence of Toll-Like Receptor Signaling , 2006, Science.

[11]  J L Turk,et al.  Complement activation by aluminium and zirconium compounds. , 1979, Immunology.

[12]  C. Dinarello Interleukin 1 and interleukin 18 as mediators of inflammation and the aging process. , 2006, The American journal of clinical nutrition.

[13]  M. Huber,et al.  Costimulation via TCR and IL-1 receptor reveals a novel IL-1alpha-mediated autocrine pathway of Th2 cell proliferation. , 1998, Journal of immunology.

[14]  F. Martinon,et al.  NALP3 forms an IL-1beta-processing inflammasome with increased activity in Muckle-Wells autoinflammatory disorder. , 2004, Immunity.

[15]  P. Weller,et al.  Pivotal Advance: Eosinophils mediate early alum adjuvant‐elicited B cell priming and IgM production , 2008, Journal of leukocyte biology.

[16]  V. Dixit,et al.  Cryopyrin activates the inflammasome in response to toxins and ATP , 2006, Nature.

[17]  J Fernando Bazan,et al.  IL-33, an interleukin-1-like cytokine that signals via the IL-1 receptor-related protein ST2 and induces T helper type 2-associated cytokines. , 2005, Immunity.

[18]  James E. Evans,et al.  Molecular identification of a danger signal that alerts the immune system to dying cells , 2003, Nature.

[19]  V. Dixit,et al.  Differential activation of the inflammasome by caspase-1 adaptors ASC and Ipaf , 2004, Nature.

[20]  J. Brewer,et al.  Interleukin‐18 plays a role in both the alum‐induced T helper 2 response and the T helper 1 response induced by alum‐adsorbed interleukin‐12 , 2003, Immunology.

[21]  F. Sutterwala,et al.  The Inflammasome: First Line of the Immune Response to Cell Stress , 2006, Cell.

[22]  P. Marrack,et al.  How do adjuvants work? Important considerations for new generation adjuvants. , 2007, Immunity.

[23]  M. Jenkins,et al.  Inflammatory cytokines provide a third signal for activation of naive CD4+ and CD8+ T cells. , 1999, Journal of immunology.

[24]  F. Re,et al.  Aluminum Hydroxide Adjuvants Activate Caspase-1 and Induce IL-1β and IL-18 Release1 , 2007, The Journal of Immunology.

[25]  F. Martinon,et al.  Gout-associated uric acid crystals activate the NALP3 inflammasome , 2006, Nature.

[26]  R. Hayward Stress , 2005, The Lancet.

[27]  S. Akira,et al.  Toll-like receptors control activation of adaptive immune responses , 2001, Nature Immunology.

[28]  P. Marrack,et al.  Promotion of B Cell Immune Responses via an Alum-Induced Myeloid Cell Population , 2004, Science.

[29]  I. Homma,et al.  IL-1 is required for allergen-specific Th2 cell activation and the development of airway hypersensitivity response. , 2003, International immunology.

[30]  Rajesh K. Gupta,et al.  Adjuvants--a balance between toxicity and adjuvanticity. , 1993, Vaccine.