Particulate Adjuvant and Innate Immunity: Past Achievements, Present Findings, and Future Prospects

Figures & data

FIGURE 1.  Proposed mechanisms of particulate adjuvants (alum, MSU, silica) in innate immunity. Alum induces cell death, and the damaged host cells, such as macrophages and neutrophils, release genomic DNA and uric acid as DAMPs. The recognition mechanisms of genomic DNA are still unclear, but the TBK-1-IRF3 axis plays an important part in IgE production and iMono/iDC migration via the IL-12p80 production. The released uric acid forms MSU crystals, which are recognized by lipid sorting on DCs. The engulfed MSU crystals trigger the activation of Syk and PI3Kδ, and induce inflammatory cells or a strong interaction between DCs and CD4⁺ T cells. However, the released uric acid has not been shown to form crystals at the site of alum injection. Alum and silica stimulate macrophages and DCs to produce NLRP3 inflammasome-dependent IL-1β and IL-18. These cytokines contribute (at least in part) to acute inflammation and Th2 activation. Macrophages and DCs also induce PGE₂ in response to alum and silica via Syk activation. PGE₂ is involved in IgE production. iMonos: inflammatory monocytes; iDCs: inflammatory DCs.

TABLE 1.  Summary of the effect of particulate (alum) adjuvant on immune system

	Proposed mechanisms	Adjuvant activity	References
Depot effect	Antigen persistence and prolonged release	• Depot effect is not required.	33), 34)
IL-4-producing cells and IL-4 signals	Th2 and IgE induction	• Eosinophils and basophils are not required.	37), 38)
		• IL-4 is required for IgE production, but not for Th2 cell differentiation.	40), 41)
MyD88 pathway and TLRs	Innate cell activation	• MyD88 and TLRs are not required.	42), 43)
NLRP3 Inflammasome	Activation of NLRP3 inflammasome and IL-1β, IL-18 release	• The involvement of inflammasome in adjuvant activity remain unclear.	27), 37), 44) 50)∼52)
Uric acid(MSU crystal)	Released from damaged cells by alumWork as DAMPs	• Th2 induction by inflammatory monocytes and DCs via Syk and PI3 kinase activation.	25), 57)
Lipid mediator	Induced from macrophage and DCs by alum or silica	• PGE2 is induced by Syk activation and promote IgE production.	17)
Nucleic acid (DNA)	Released from damaged cells by alum Work as DAMPs	• Th2 and IgE induction by inflammatory monocytes and DCs through the secretion of IL-12p80 and activation of TBK1-IRF3.	75)