High Mitochondrial Respiration and Glycolytic Capacity Represent a Metabolic Phenotype of Human Tolerogenic Dendritic Cells

Malinarich, Frano; Duan, Kaibo; Hamid, Raudhah Abdull; Au, Bijin; Lin, Wu Xue; Poidinger, Michael; Fairhurst, Anna‐Marie; Connolly, John E.

doi:10.4049/jimmunol.1303316

Cited by 172 publications

(187 citation statements)

References 35 publications

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“…Metabolic studies in macrophages have revealed differential pathways regulated during differentiation into M1 and M2 phenotypes (7–10). Similar studies have been undertaken for T helper cell subsets (6, 11, 12), dendritic cells (13), and to a limited extent also in monocytes (5). In well-perfused inflamed tissues like the synovial membrane in rheumatoid arthritis, where nutrients are in ample supply, the massively upregulated glycolytic flux of activated monocytes and macrophages is sustained by high glucose consumption.…”

Section: Introductionmentioning

confidence: 64%

Fatty Acid Oxidation Compensates for Lipopolysaccharide-Induced Warburg Effect in Glucose-Deprived Monocytes

et al. 2017

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Monocytes enter sites of microbial or sterile inflammation as the first line of defense of the immune system and initiate pro-inflammatory effector mechanisms. We show that activation with bacterial lipopolysaccharide (LPS) induces them to undergo a metabolic shift toward aerobic glycolysis, similar to the Warburg effect observed in cancer cells. At sites of inflammation, however, glucose concentrations are often drastically decreased, which prompted us to study monocyte function under conditions of glucose deprivation and abrogated Warburg effect. Experiments using the Seahorse Extracellular Flux Analyzer revealed that limited glucose supply shifts monocyte metabolism toward oxidative phosphorylation, fueled largely by fatty acid oxidation at the expense of lipid droplets. While this metabolic state appears to provide sufficient energy to sustain functional properties like cytokine secretion, migration, and phagocytosis, it cannot prevent a rise in the AMP/ATP ratio and a decreased respiratory burst. The molecular trigger mediating the metabolic shift and the functional consequences is activation of AMP-activated protein kinase (AMPK). Taken together, our results indicate that monocytes are sufficiently metabolically flexible to perform pro-inflammatory functions at sites of inflammation despite glucose deprivation and inhibition of the LPS-induced Warburg effect. AMPK seems to play a pivotal role in orchestrating these processes during glucose deprivation in monocytes.

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Section: Introductionmentioning

confidence: 64%

Fatty Acid Oxidation Compensates for Lipopolysaccharide-Induced Warburg Effect in Glucose-Deprived Monocytes

et al. 2017

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“…50 Tolerogenic DCs display enhanced glycolytic capacity and ROS production with respect to mature pro-inflammatory DCs. 51 PM significantly increases intracellular ROS in human DCs, which were inhibited by alum. Recently, D-mannose treatment increased ROS production in T cells compared with TCR stimulation alone.…”

Section: Discussionmentioning

confidence: 93%

Alum impairs tolerogenic properties induced by allergoid‐mannan conjugates inhibiting mTOR and metabolic reprogramming in human DCs

Benito-Villalvilla

Soria

Pérez‐Diego

et al. 2019

Allergy

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Background Polymerized allergoids conjugated to mannan (PM) are suitable vaccines for allergen‐specific immunotherapy (AIT). Alum remains the most widely used adjuvant in AIT, but its way of action is not completely elucidated. The better understanding of the mechanisms underlying alum adjuvanticity could help to improve AIT vaccine formulations. Objective We sought to investigate the potential influence of alum in the tolerogenic properties imprinted by PM at the molecular level. Methods Flow cytometry, ELISAs, cocultures, intracellular staining and suppression assays were performed to assess alum and PM effects in human dendritic cells (DCs). BALB/c mice were immunized with PM alone or adsorbed to alum. Allergen‐specific antibodies, splenocyte cytokine production and splenic forkhead box P3 (FOXP3)+ regulatory T (Treg) cells were quantified. Metabolic and immune pathways were also studied in human DCs. Results Alum decreases PD‐L1 expression and IL‐10 production induced by PM in human DCs and increases pro‐inflammatory cytokine production. Alum impairs PM‐induced functional FOXP3+ Treg cells and promotes Th1/Th2/Th17 responses. Subcutaneous immunization of mice with PM plus alum inhibits in vivo induction of Treg cells promoted by PM without altering the capacity to induce functional allergen‐specific blocking antibodies. Alum inhibits mTOR activation and alters metabolic reprogramming by shifting glycolytic pathways and inhibiting reactive oxygen species (ROS) production in PM‐activated DCs, impairing their capacity to generate functional Treg cells. Conclusion We uncover novel mechanisms by which alum impairs the tolerogenic properties induced by PM, which might well contribute to improve the formulation of novel vaccines for AIT.

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“…This conclusion is based on metabolic analyses of tolerogenic human DCs (Malinarich et al, 2015), as well as the fact that resveratrol, a drug that promotes OXP HOS, and vitamin-D3 and dexamethasone, which promote the expression of genes related to OXP HOS, enhance DC tolerogenicity (Rachamim et al, 1995;Švajger et al, 2010;Ferreira et al, 2015). Recent work has emphasized the complexity of the role of lipid metabolism in the regulation of DC function.…”

Section: Switching To Warburg Metabolism Allows Cellular Activation Amentioning

confidence: 99%

Immunometabolism governs dendritic cell and macrophage function

O’Neill¹,

Pearce²

2016

J Cell Biol

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The main challenge of metabolic pathways has always been their complexity. This stems from the number of metabolites (which intracellularly can run into the thousands), their chemical complexity, and the sophisticated regulation of the enzymes that control them. Recent discoveries on the role of metabolic pathways in immune cell function have brought the burgeoning area of immunometabolism to the forefront for many immunologists. In this review, we will discuss recent findings in macrophages and DCs, critical cell types for both innate and adaptive immunity. A primary goal for immunologists is to uncover the molecular players in processes that provide a detailed account of how the effector functions of immune cells are controlled. These processes become dysregulated in disease. The analysis of metabolic reprogramming in macrophages and DCs provides new insights into how these cells perform their functions, including cytokine production, phagocytosis, or antigen presentation. The somewhat surprising finding is that metabolic processes such as glycolysis, the Krebs cycle, and fatty acid metabolism have highly specific effects on macrophage and DC function. The manipulation of these pathways can dramatically alter the functioning of these cells in specific ways, rather than simply being involved in energy generation or general biosynthesis. Metabolic reprogramming as a phenomenon is therefore joining other key immunoregulatory events that govern the nature of the immune response, both in health and disease. What is metabolic reprogramming?A simple view of metabolic reprogramming is that it reflects the responses of cells to critical changes in the environment. For example, under normoxic conditions, cells can use oxidative phosphorylation (OXP HOS) to generate ATP. Critical components of the electron transport chain (ETC) use NADH and FADH generated as a result of reactions in the Krebs cycle, which in turn is fueled by glucose, fatty acids, and glutamine. In contrast, when O 2 tensions are low, cells can to a greater or lesser degree generate ATP through glycolysis and independently of OXP HOS, but this pathway is highly dependent on glucose as a sole fuel source. The core metabolic pathways are essential for interchanging carbons between sugars, fatty acids, nucleic acids, and proteins, and therefore, metabolic flexibility can play a critical role as prevailing nutrient and oxygen conditions change. This can be of great importance if a cell is faced with differing functional demands. A critical point from the perspective of this review is that recent work has emphasized the fact that changes in key metabolic regulatory events in immune cells can be initiated not only by nutrient and oxygen conditions, but also in reprogramming events downstream of ligation of pattern recognition receptors (PRRs), cytokine receptors, and/or Ag receptors (and likely other receptors). Thus, in immune cells, there is the potential for metabolic changes to occur in response to instructional signals received from other cells or from ch...

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High Mitochondrial Respiration and Glycolytic Capacity Represent a Metabolic Phenotype of Human Tolerogenic Dendritic Cells

Cited by 172 publications

References 35 publications

Fatty Acid Oxidation Compensates for Lipopolysaccharide-Induced Warburg Effect in Glucose-Deprived Monocytes

Fatty Acid Oxidation Compensates for Lipopolysaccharide-Induced Warburg Effect in Glucose-Deprived Monocytes

Alum impairs tolerogenic properties induced by allergoid‐mannan conjugates inhibiting mTOR and metabolic reprogramming in human DCs

Immunometabolism governs dendritic cell and macrophage function

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