IL-33 released by alum is responsible for early cytokine production and has adjuvant properties

Abstract

Human vaccines have used aluminium-based adjuvants (alum) for >80 years despite incomplete understanding of how alum enhances the immune response. Alum can induce the release of endogenous danger signals via cellular necrosis which elicits inflammation-associated cytokines resulting in humoral immunity. IL-33 is proposed to be one such danger signal that is released from necrotic cells. Therefore, we investigated whether there is a role for IL-33 in the adjuvant activity of alum. We show that alum-induced cellular necrosis results in elevated levels of IL-33 following injection in vivo. Alum and IL-33 induce similar increases in IL-5, KC, MCP-1, MIP-1α and MIP-1β; many of which are dependent on IL-33 as shown in IL-33 knockout mice or by using an IL-33-neutralizing recombinant ST2 receptor. Furthermore, IL-33 itself functions as an adjuvant that, while only inducing a marginal primary response, facilitates a robust secondary response comparable to that observed with alum. However, IL-33 is not absolutely required for alum-induced antibody responses since alum mediates similar humoral responses in IL-33 knockout and wild-type mice. Our results provide novel insights into the mechanism of action behind alum-induced cytokine responses and show that IL-33 is sufficient to provide a robust secondary antibody response independently of alum.

A Guide to IL‐1 family cytokines in adjuvanticity

“…Elevated IL‐33 concentrations were detected locally after mice were injected with alum intraperitoneally. Lack of IL‐33 or impaired IL‐33 signalling reduced local cytokine and chemokine secretion (IL‐5, IL‐13, MCP‐1, G‐CSF) but IL‐33 was not required for alum‐induced antibody responses . In conclusion, although IL‐1 and IL‐33 contribute to alum‐induced innate responses, they seem to be dispensable for alum‐induced IgG responses.…”

“…Adjuvants such as CAF 01, AS 04 or AS 02 containing ligands of innate receptors, promote upregulation of costimulatory molecules and cytokine secretion in dendritic cells ( DC s) . They may also indirectly activate APC s by inducing cell damage and release of DAMP s or alarmins or different types of programmed cell death that regulate nonconventional secretion of IL ‐1 family cytokines influencing differentiation of T cells . [Colour figure can be viewed at wileyonlinelibrary.com]…”

Interleukin‐33 (IL‐33): A nuclear cytokine from the IL‐1 family

“…Other agents that cause cellular damage or necrotic cell death were found to induce rapid release of IL‐33 in extracellular fluids. For instance, bee venom phospholipase A2, a major allergen that is known to cause membrane damage, and alum, a potent adjuvant that induces cellular necrosis, were found to induce IL‐33 release in peritoneal fluids 30 minutes after intraperitoneal injection . In addition, IL‐33 has been shown to be released in plasma after necroptosis, a specialized pathway of programmed necrosis …”

The Role of IL-33-Dependent Inflammation in the Tumor Microenvironment

“…In addition, IL-33 injected together with the NP-CGG model antigen increased NP-specific IgM titers in the primary response and T cell-dependent NP-specific IgG1 titers after antigen boost. This indicates that IL-33 can induce robust antigen-specific antibody responses (105). IL-33 was also reported to reduce the accumulation of MDSCs in the spleen and tumor microenvironment, and to decrease the immunosuppressive activity of these cells, which limited tumor growth (106).…”