The vaccine adjuvant MPLA activates glycolytic metabolism in mouse mDC by a JNK-dependent activation of mTOR-signaling

Blanco-Pérez, Frank; Goretzki, Alexandra; Wolfheimer, Sonja; Schülke, Stefan

doi:10.1016/j.molimm.2018.12.029

Cited by 15 publications

(13 citation statements)

References 49 publications

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“…This early glycolytic reprogramming by TLRs is required for upregulation of co-stimulatory molecules, production of pro-inflammatory cytokines, CCR7 oligomerization, and priming T cells , Guak et al, 2018. Subsequently, DCs inhibit OXPHOS via NO and rely on aerobic glycolysis for their survival, especially after sustained exposure to TLR-agonists (Everts et al, 2012, Blanco-Perez et al, 2019. Based on the augmented ability of ADJ-treated DCs to activate T cells, we hypothesized that metabolic reprogramming plays a distinctive role in this process.…”

Section: Adj Enhances Cross-presentation Without Glycolytic Reprogrammentioning

confidence: 99%

Carbomer-based Nano-Emulsion Adjuvant Enhances Dendritic Cell Cross-presentation via Lipid Body Formation Independent of Glycolysis

Suresh

Lee

Kingstad-Bakke

et al. 2020

Preprint

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ADJ induces inflammasome activation in DCs, but deficiency for NLRP3, ASC or caspase 1 did not affect ADJ-mediated cross-presentationNext, we examined the effects of ADJ on the expression profiles of cytokines, chemokines and canonical cell surface markers of DC activation. Compared to untreated DCs, ADJ-treated DCs showed statistically significant, yet modest increases in expression of CD40, CD80, and CD86; no significant differences in expression were observed for MHC-I, MHC-II, or CCR7 (Fig. 1C).ADJ-treated DCs produced higher levels of IL-12 (p70), TNF-, IL-1, CCL3, CCL4, CXCL1, and RANTES, as compared to untreated DCs; no significant differences in expression were observed for IL-6, IL-10, and IFN- (Fig. 1D). Particularly, ADJ-stimulated DCs also produced significantly elevated levels of IL-1 and IL-18 (Fig. 1D), which is suggestive of inflammasome activation. Since inflammasome activation has been implicated in modulation of antigen presentation by DCs (Sokolovska et al., 2013, Li et al., 2019, we performed B3Z assays using DCs deficient in NLRP3, ASC, or caspase 1 to interrogate whether inflammasome activation is required for ADJ-induced cross-presentation in BMDCs. Surprisingly, loss of NLRP3, ASC or caspase 1 activity did not affect ADJ-induced cross-presentation by DCs, in vitro (Fig. 1E). To validate whether caspase 1 is required for cross-presentation in vivo, we immunized cohorts of wild type (WT) and caspase 1-deficient mice with ADJ+OVA, and quantified OVA SIINFEKLspecific CD8 T cells in spleens using MHC I tetramers at day 8 after immunization. Consistent with our results from B3Z assays, caspase 1 deficiency did not significantly affect the activation of SIINFEKL-specific CD8 T cells in spleens (Fig. 1F), suggesting that caspase 1 is not essential for ADJ-driven cross-presentation to CD8 T cells in vivo.

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Section: Adj Enhances Cross-presentation Without Glycolytic Reprogrammentioning

confidence: 99%

Carbomer-based Nano-Emulsion Adjuvant Enhances Dendritic Cell Cross-presentation via Lipid Body Formation Independent of Glycolysis

Suresh

Lee

Kingstad-Bakke

et al. 2020

Preprint

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“…Other studies have shown that MPL-A induces JNK- and mTOR-dependent signaling in macrophages and dendritic cells. This pathway leads to increases in the metabolic activity of macrophages for antimicrobial purposes [75] and the production of proinflammatory cytokines in dendritic cells [76].…”

Section: Adjuvants Of Bacterial Originmentioning

confidence: 99%

Chemical and Immunological Characteristics of Aluminum-Based, Oil-Water Emulsion, and Bacterial-Origin Adjuvants

Martiñón

Cisneros

Villicana

et al. 2019

Journal of Immunology Research

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Adjuvants are a diverse family of substances whose main objective is to increase the strength, quality, and duration of the immune response caused by vaccines. The most commonly used adjuvants are aluminum-based, oil-water emulsion, and bacterial-origin adjuvants. In this paper, we will discuss how the election of adjuvants is important for the adjuvant-mediated induction of immunity for different types of vaccines. Aluminum-based adjuvants are the most commonly used, the safest, and have the best efficacy, due to the triggering of a strong humoral response, albeit generating a weak induction of cell-mediated immune response. Freund’s adjuvant is the most widely used oil-water emulsion adjuvant in animal trials; it stimulates inflammation and causes aggregation and precipitation of soluble protein antigens that facilitate the uptake by antigen-presenting cells (APCs). Adjuvants of bacterial origin, such as flagellin, E. coli membranes, and monophosphoryl lipid A (MLA), are known to potentiate immune responses, but their safety and risks are the main concern of their clinical use. This minireview summarizes the mechanisms that classic and novel adjuvants produce to stimulate immune responses.

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“…The ability of MPLA to modulate immune responses has been well studied before [20,32]. Activation of dendritic cells (DC) was reported to contribute to humoral immune responses induced by live rabies vaccine [19,31,33].…”

Section: Mpla Facilitates the Maturation Of Bmdc Via A Tlr4-dependentmentioning

confidence: 99%

Monophosphoryl-Lipid A (MPLA) is an Efficacious Adjuvant for Inactivated Rabies Vaccines

Chen

Zhang

et al. 2019

Viruses

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Rabies, as one of the most threatening zoonoses in the world, causes a fatal central nervous system (CNS) disease. So far, vaccination with rabies vaccines has been the most effective measure to prevent and control this disease. At present, inactivated rabies vaccines are widely used in humans and domestic animals. However, humoral immune responses induced by inactivated rabies vaccines are relatively low and multiple shots are required to achieve protective immunity. Supplementation with an adjuvant is a practical way to improve the immunogenicity of inactivated rabies vaccines. In this study, we found that monophosphoryl-lipid A (MPLA), a well-known TLR4 agonist, could significantly promote the maturation of bone marrow-derived dendritic cells (BMDC) through a TLR4-dependent pathway in vitro and the maturation of conventional DCs (cDCs) in vivo. We also found that MPLA, serving as an adjuvant for inactivated rabies vaccines, could significantly facilitate the generation of T follicular helper (Tfh) cells, germinal center (GC) B cells, and plasma cells (PCs), consequently enhancing the production of RABV-specific total-IgG, IgG2a, IgG2b, and the virus-neutralizing antibodies (VNAs). Furthermore, MPLA could increase the survival ratio of mice challenged with virulent RABV. In conclusion, our results demonstrate that MPLA serving as an adjuvant enhances the intensity of humoral immune responses by activating the cDC–Tfh–GC B axis. Our findings will contribute to the improvement of the efficiency of traditional rabies vaccines.

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The vaccine adjuvant MPLA activates glycolytic metabolism in mouse mDC by a JNK-dependent activation of mTOR-signaling

Cited by 15 publications

References 49 publications

Carbomer-based Nano-Emulsion Adjuvant Enhances Dendritic Cell Cross-presentation via Lipid Body Formation Independent of Glycolysis

Carbomer-based Nano-Emulsion Adjuvant Enhances Dendritic Cell Cross-presentation via Lipid Body Formation Independent of Glycolysis

Chemical and Immunological Characteristics of Aluminum-Based, Oil-Water Emulsion, and Bacterial-Origin Adjuvants

Monophosphoryl-Lipid A (MPLA) is an Efficacious Adjuvant for Inactivated Rabies Vaccines

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