Crucial role for the Nalp3 inflammasome in the immunostimulatory properties of aluminium adjuvants

By S. Eisenbarth, O. Colegio, William O'Connor, F. Sutterwala, R. Flavell. Nature, 2008

1,601 citations recorded by the source corpus.

Aluminium adjuvants, typically referred to as ‘alum’, are the most commonly used adjuvants in human and animal vaccines worldwide, yet the mechanism underlying the stimulation of the immune system by alum remains unknown. Toll-like receptors are critical in sensing infections and are therefore common targets of various adjuvants used in immunological studies. Although alum is known to induce the production of proinflammatory cytokines in vitro, it has been repeatedly demonstrated that alum does not require intact Toll-like receptor signalling to activate the immune system. Here we show that aluminium adjuvants activate an intracellular innate immune response system called the Nalp3 (also known as cryopyrin, CIAS1 or NLRP3) inflammasome. Production of the pro-inflammatory cytokines interleukin-1β and interleukin-18 by macrophages in response to alum in vitro required intact inflammasome signalling. Furthermore, in vivo, mice deficient in Nalp3, ASC (apoptosis-associated speck-like protein containing a caspase recruitment domain) or caspase-1 failed to mount a significant antibody response to an antigen administered with aluminium adjuvants, whereas the response to complete Freund’s adjuvant remained intact. We identify the Nalp3 inflammasome as a crucial element in the adjuvant effect of aluminium adjuvants; in addition, we show that the innate inflammasome pathway can direct a humoral adaptive immune response. This is likely to affect how we design effective, but safe, adjuvants in the future.

Subfields: Immunology, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/a8d9bd1a04704d03d3ab6211d1e268e04add30e0

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In Immunology

1. Guido Kroemer
2. L. Zitvogel
3. J. Tschopp
4. G. Núñez
5. Luke A. O'Neill
6. Bali Pulendran
7. Shizuo Akira
8. E. Latz

In Molecular Biology

1. J. Tschopp
2. G. Núñez
3. E. Latz
4. L. Franchi
5. Guido Kroemer
6. J. Ting
7. F. Sutterwala
8. H. Kono

Citations in the corpus

• Inflammasomes in health and disease (2012, background): “Exposure of macrophages to alum in vitro leads to the NLRP3-dependent activation of caspase-1, and several studies have demonstrated that NLRP3 inflammasome-deficient mice have defects in alum-induced adaptive immune responses in vivo”
• Cutting Edge: Alum Adjuvant Stimulates Inflammatory Dendritic Cells through Activation of the NALP3 Inflammasome (2008, methodology): “This striking-difference may be due to a different experimental setup, as in their study Ab generation was determined after an intranasal challenge with OVA (16) whereas we boosted mice by injecting OVA i.”
• The sterile inflammatory response (2010, methodology): “Subsequent studies by a number of groups found that NLRP3-deficient macrophages failed to produce mature IL-1β after stimulation with a variety of sterile particulate particles including silica (56, 57), alum (24, 56, 58, 59, 98), asbestos (57), and cholesterol crystals (Duewell et.”
• Mechanisms of Action of Adjuvants (2013, background): “Using NLRP3, ASC and caspase-1 knockout mice, Eisenbarth et al. (2008) showed that the NLRP3 inflammasome is a crucial component in the adjuvant activity of alum.”
• Antimicrobial activity of mucosal-associated invariant T cells (2010, background): “19 ), the cytoplasmic receptor NLRP3 and adaptor AS”
• Overview of the Immune Response (2003, background): “If any one of NALP3, ASC, or caspase-1 is absent or defective, then alum can no longer serve to augment the antibody response.(88)”