Aluminum Hydroxide Adjuvants Activate Caspase-1 and Induce IL-1β and IL-18 Release

Abstract

Aluminum hydroxide (Alum) is the only adjuvant approved for routine use in humans, although the basis for its adjuvanticity remains poorly understood. In this study, we show that Alum activates caspase-1 and induce secretion of mature IL-1β and IL-18. Human PBMC or dendritic cells stimulated with pure TLR4 and TLR2 agonists released only traces of IL-1β or IL-18, despite the fact that the IL-1β mRNA was readily induced by both TLR agonists. In contrast, cells costimulated with TLR agonists plus Alum released large amount of IL-1β and IL-18. Alum-induced IL-1β and IL-18 production was not due to enhancement of TLR signaling but rather reflected caspase-1 activation and in mouse dendritic cells occurred in a MyD88-independent fashion. Secretion of other proinflammatory cytokines such as IL-8 was not affected by Alum treatments. However, TLR-induced production of IL-10 was increased and that of IFN-γ-inducible protein decreased by Alum cotreatment. Considering the immunostimulatory activities of these cytokines and the ability of IL-1β to act as adjuvant, our results suggest a mechanism for the adjuvanticity of Alum.

The controversial relationship between NLRP3, alum, danger signals and the next‐generation adjuvants

“…Thus, not surprisingly two authors reported a failure in IL-1b secretion in response to aluminium/alum powder resuspended in physiological buffer [10,12]. Therefore, although it has been shown that Imject s Alum is able to activate caspase-1 in vitro as much as licensed aluminium adjuvants do [10], the in vivo effects of a formulation with different physico-chemical parameters are unpredictable and could partially account for the differences observed in the above-mentioned studies [13,14,16,17].…”

“…Another issue is the physico-chemical form of alum, which could be critical [10,20]. Some experiments [14,17] were performed with Imject s Alum, a proprietary formulation available for research purposes, which is a 1:1 mixture of aluminium hydroxide and magnesium hydroxide that differs considerably from the alum adjuvants licensed for human use.…”

“…2010. 40: 595-653 LPS-primed human and murine DC in vitro [10], a reminder of the doublestep requirement for inflammasome activation triggered by other particulates, such as silica or asbestos [11]. The following year, it was found that uric acid is induced by alum in vivo and is responsible for alum immunostimulatory properties, suggesting a possible, indirect involvement of the NLRP3 inflammasome [5], which can be activated by monosodium urate (MSU) crystals [12].…”

Alum adjuvanticity: Unraveling a century old mystery

“…It has been reported that alum synergizes with TLR agonists in vitro to stimulate IL-1b production from human PBMC [18]. The paper by Franchi and Nfflaeez in this issue of the European Journal of Immunology [19] and the recent paper by Eisenbarth et al [20] have clarified the molecular mechanism of alum and TLR agonist cross-talk in mouse macrophages.…”

Collagen Type II and a Thermo-Responsive Polymer of N-Isopropylacrylamide Induce Arthritis Independent of Toll-Like Receptors

“…Recent studies have also shown that the commonly used adjuvant alum induced the release of IL-1␤, IL-18, and IL-33 52,53 that is mediated by NALP3. 54 Hence, to check whether adjuvancy of PNiPAAm also involves the inflammasome pathway, we analyzed IL-1␤ levels in the sera from PNiPAAm-CII-immunized mice and compared it with CII emulsified with Freund's adjuvant(s).…”