The Nlrp3 inflammasome is critical for aluminium hydroxide-mediated IL-1beta secretion but dispensable for adjuvant activity.
Aluminum hydroxide (alum) is the most widely used adjuvant in human vaccines, but the immune mechanisms that are activated by alum remain poorly understood. Alum has recently been shown to promote caspase-1 activation and IL-1beta secretion, but the cellular pathways involved remain elusive. Here we report that the release of IL-1beta triggered by alum is abrogated in macrophages deficient in the NLR family, pyrin domain containing 3 (Nlrp3) protein and the apoptosis-associated speck-like protein containing a caspase recruitment domain (Asc) but not the NLR family, CARD domain containing 4 (Nlrc4) protein. The requirement of the Nlrp3 inflammasome was specific for IL-1beta in that secretion of TNF-alpha was independent of Nlrp3 or Asc. Consistently, processing of pro-caspase-1 induced by alum was abolished in macrophages lacking Nlrp3 or Asc. Unlike caspase-1 processing and IL-1beta secretion triggered by LPS, alum-mediated activation of the inflammasome did not require exogenous ATP. Importantly, induction of IgG production against human serum albumin by alum was unimpaired in mice deficient in Nlrp3. These results indicate that alum induces IL-1beta via the Nlrp3 inflammasome but this activity is dispensable for alum-mediated adjuvant activity.
Franchi
Luigi
L
Department of Pathology and Comprehensive Cancer Center, The University of Michigan Medical School, Ann Arbor, MI 48109, USA.
Núñez
Gabriel
G
D000276:Adjuvants, Immunologic / Q000494:pharmacology*; D000536:Aluminum Hydroxide / Q000494:pharmacology*; D000818:Animals; D002352:Carrier Proteins / Q000502:physiology*; D020170:Caspase 1 / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D007249:Inflammation / Q000276:immunology*; D053583:Interleukin-1beta / Q000378:metabolism*; D051379:Mice; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein
D000276:Adjuvants, Immunologic; D002352:Carrier Proteins; D053583:Interleukin-1beta; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse; D000536:Aluminum Hydroxide; D020170:Caspase 1