Recent data demonstrate that alum targets NOD-like receptor protein 3 (NLRP3 or NALP3) to mediate caspase-1 activation and IL-1β release in lipopolysaccharide- (LPS-) primed macrophages [36]. NLRP3 interacts with Cardinal and ASC (apoptosis-associated speck-like protein) to form a caspase-1-activating complex called inflammasome, which, in turn, mediates the activation of proIL-1β, proIL-18, and Cilengitide proIL-33

into their active forms (Figure 2) [34]. However, in vivo data demonstrated that NLRP3 is dispensable for the adjuvant activity [36]. Nevertheless, other groups have reached conflicting conclusions. Eisenbarth Inhibitors,research,lifescience,medical et al. [37] and Li et al. [38] found an abrogation of the antibody responses to coadministered antigen in absence of NALP3 signaling, whereas Kool et al. [39] found only partial inhibition of the response. However, these results may be explained by the fact that different Inhibitors,research,lifescience,medical alum formulations were used in each study or different levels of TLR (Toll like receptor) agonist were used [40]. Figure 2 Scheme of the potential interaction of alum with the

NALP3 inflammasome. Caspase-1 is activated, which in turn, promotes Inhibitors,research,lifescience,medical the activation of proinflammatory cytokines IL-β, IL-18, and IL-33. This process is abrogated by actin polymerization inhibitors, … Other studies have suggested that NALP3 could be stimulated though indirect mechanisms. Kool et al. found that following alum administration, an increase in the endogenous danger signal uric acid happened. Neutralization of uric acid with uricase led to an inhibition of the inflammatory response

induced by alum [33]. There are several investigators which study the immune response achieved after combining Inhibitors,research,lifescience,medical synthetic peptides with alum. For instance, a phase I clinical trial was conducted with the long synthetic peptide GLURP85-213 of Plasmodium falciparum combined with either alum or Montanide ISA as adjuvants [41]. Formulations were administered subcutaneously Inhibitors,research,lifescience,medical with 10, 30, or 100μg peptide doses at days 0, 30, and 120. Although serious adverse events were not observed, adverse events MTMR9 were more prevalent in the Montanide ISA group. On the other hand, both vaccines generated antibodies with capacity to mediate growth-inhibitory activity against P. falciparum in vitro. However, nowadays, alum adjuvant is being replaced by other systems that improve the immune response achieved, and generally, it is used as a control or in combination with other adjuvants. For example, Raman et al. investigated the immunomodulatory effects of two types of CpG adjuvants intranasally administered with five synthetic peptide antigens of Plasmodium vivax in alum and microparticles. The addition of alum to CpG increased four-fold the antibody titers and triggered a predominance of IgG2a/2b isotypes.