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Abstract
Alum adjuvanticity is still an unknown mechanism despite the frequent use as vaccine adjuvant in humans. Here we show that Alum-induced inflammasome activation in vitro and in vivo is mediated by the G protein-coupled receptor GPRC6A. The Alum-induced humoral response in vivo was independent of the inflammasome because Nlrp3−/− and ASC−/− mice responded normally to Alum and blockade of IL-1 had no effect on antibody production. In contrast, Alum adjuvanticity was increased in GPRC6A−/− mice resulting in increased antibody responses and increased Th2 cytokine concentrations compared to wildtype mice. In vitro activation of GPRC6A−/− splenic B cells also induced increased IgG1 concentrations compared to wildtype B cells. For the first time, we show GPRC6A expression in B cells, contributing to the direct effects of Alum on those cells. B cell produced immunostimulatory IL-10 is elevated in GPRC6A−/− B cells in vitro and in vivo. Our results demonstrate a dual role of GPRC6A in Alum adjuvanticity. GPCR6A activation by Alum leads to the initiation of innate inflammatory responses whereas it is an important signal for the limitation of adaptive immune responses induced by Alum, partially explained by B cell IL-10.
Highlights
Aluminum salts (Alum) are commonly used adjuvants for routine human vaccination, its mode of action remains unclear
Secretion of IL-1β is strongly reduced in associated speck-like protein (ASC)−/− (Fig. 1a), Nlrp3−/− (Fig. 1a) and Caspase1−/− (Supplementary Fig. S1) macrophages
Aluminduced IL-1α secretion is only minimal reduced in ASC−/− and Nlrp3−/− macrophages (Fig. 1a)
Summary
Aluminum salts (Alum) are commonly used adjuvants for routine human vaccination, its mode of action remains unclear. They induce a type 2 immune response which is characterized by the appearance of antigen-specific IgG1 and IgE antibodies in the serum (reviewed in[1]). One hypothesis was that Alum serves as a depot in the body from which the antigen is released slowly[3]. We show that Alum adjuvanticity is increased in GPRC6A−/− mice resulting in increased antibody responses and increased Th2 cytokine concentrations compared to wildtype mice. We observed no participation of Nlrp[3], ASC and IL-1 in Alum-induced antibody responses. We show that splenic B cells express GPRC6A and the in vitro induced IgG1 is increased in B cell cultures from GPRC6A−/− compared to wildtype mice
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