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

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Abstract
Vaccines are frequently administered together with an adjuvant, a compound that boosts the immune response to the vaccine's active ingredient. One of the most popular adjuvants is aluminium hydroxide, or alum, which has been used for 80 years or so, because it works. How it works was not known — until now. Aluminium salts are shown to activate the Nalp3 inflammasome, an intracellular innate immune response system active in macrophages. Understanding how this widely used adjuvant acts could help in the design of more powerful, more specific adjuvants working in the same way. The mechanism by which the widely used vaccine adjuvant alum acts on the immune system has been unclear to-date. This paper shows that alum-mediated stimulation of the adaptive immune response requires activation of the Nalp3 inflammasome in antigen presenting cells. 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 system1,2. 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.