Inflammasome-Dependent and -Independent IL-18 Production Mediates Immunity to the ISCOMATRIX Adjuvant

Abstract

Adjuvants are an essential component of modern vaccines and used for their ability to elicit immunity to coadministered Ags. Many adjuvants in clinical development are particulates, but how they drive innate and adaptive immune responses remains poorly understood. Studies have shown that a number of vaccine adjuvants activate inflammasome pathways in isolated APCs. However, the contribution of inflammasome activation to vaccine-mediated immunity in vivo remains controversial. In this study, we evaluated immune cell responses to the ISCOMATRIX adjuvant (IMX) in mice. Like other particulate vaccine adjuvants, IMX potently activated the NALP-3–ASC–Caspase-1 inflammasome in APCs, leading to IL-1β and IL-18 production. The IL-18R pathway, but not IL-1R, was required for early innate and subsequent cellular immune responses to a model IMX vaccine. APCs directly exposed to IMX underwent an endosome-mediated cell-death response, which we propose initiates inflammatory events locally at the injection site. Importantly, both inflammasome-related and -unrelated pathways contributed to IL-18 dependence in vivo following IMX administration. TNF-α provided a physiological priming signal for inflammasome-dependent IL-18 production by APCs, which correlated with reduced vaccine-mediated immune cell responses in TNF-α– or TNFR-deficient mice. Taken together, our findings highlight an important disconnect between the mechanisms of vaccine adjuvant action in vitro versus in vivo.

Nlrp3-dependent IL-1β inhibits CD103+ dendritic cell differentiation in the gut

“…(18,23,42). Our data are concordant with a recent report on miR-223-mediated regulation of Nlrp3 expression and intestinal inflammation, describing Nlrp3-dependent elevation of IL-1, but not of IL-18, levels (20).…”

“…-/-and Nlrp3 -/-Rag1 -/-mice indicate an NLRP3-independent mechanism for IL-18 production (23,41,42). Given the potent proinflammatory function of IL-1β in the colitis model, we were interested in the role of IL-1R and IL-18R signaling in T cells.…”

Aminated nanomicelles as a designer vaccine adjuvant to trigger inflammasomes and multiple arms of the innate immune response in lymph nodes

“…In order to investigate the effects of the combined nanoadjuvant aPNM-IC on multiple arms of the innate immune response, we determined whether other inflammasome-independent proinflammatory cytokines and type I IFN were secreted in addition to inflammasome induction. 36 The secretion of IL-1β was higher in the mouse groups treated with aPNM-IC ( Figure 5A). The secretion levels of TNF-α and IL-6 were also markedly increased in the mouse groups treated with aPNM-IC compared with those treated with aPNMs or poly-(I:C) only ( Figure 5B and C).…”

Investigation of cell death caused by the Nanopatch™ and its role in vaccine delivery as a physical immune enhancer

“…In addition to inflammatory cells infiltrating to the injection site (e.g. ISCOMatrix [386]. Not only did they find that ISCOMatrix activated the NALP3, ASC, Caspase-1 inflammasome in APCs, which then resulted in IL-1β and IL-18 secretion, but also that ISCOMatrix induced rapid cellular ATP depletion and cell death in ex vivo studies using macrophages.…”

“…Examples include MPL, CpG oligonucleotide sequences, ISCOMs (immuno-stimulating complexes; ISCOMatrix), PolyI:C etc. The first three are one of the most studied and best categorised adjuvants regarding their mode of action [386,387]. MPL is licensed within the AS04 adjuvant while MPL in AS02 as well as CpG and ISCOMatrix are currently being tested in clinical trials [13,14,70,359,360,388].…”