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Review
. 2016 Jan 11;213(1):15-23.
doi: 10.1084/jem.20151570. Epub 2015 Dec 22.

Immunometabolism Governs Dendritic Cell and Macrophage Function

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Free PMC article
Review

Immunometabolism Governs Dendritic Cell and Macrophage Function

Luke A J O'Neill et al. J Exp Med. .
Free PMC article

Abstract

Recent studies on intracellular metabolism in dendritic cells (DCs) and macrophages provide new insights on the functioning of these critical controllers of innate and adaptive immunity. Both cell types undergo profound metabolic reprogramming in response to environmental cues, such as hypoxia or nutrient alterations, but importantly also in response to danger signals and cytokines. Metabolites such as succinate and citrate have a direct impact on the functioning of macrophages. Immunogenicity and tolerogenicity of DCs is also determined by anabolic and catabolic processes, respectively. These findings provide new prospects for therapeutic manipulation in inflammatory diseases and cancer.

Figures

Figure 1.
Figure 1.
Immune signals as metabolic reprogrammers in macrophages and DCs. Normoxia or hypoxia will reprogram the metabolism of cells, with normoxia promoting the Krebs cycle and oxidative phosphorylation and hypoxia promoting glycolysis, both for ATP production. In normoxia, glucose, fatty acids, and glutamine can all feed Krebs cycle, whereas for glycolysis glucose is metabolized. Immune signals can have a similar effect, with helminths driving IL-4 production to promote oxidative phosphorylation and danger signals (e.g., LPS acting via TLR4) promoting glycolysis and fatty acid synthesis. Metabolic reprogramming is therefore not only a consequence of the level of oxygen and nutrients, and instead is being driven by immune signals. The metabolism in IL-4–activated macrophages and DCs allows for long-term responses appropriate for handling parasites, whereas glycolysis is more suited to a rapid response to bacterial infection.
Figure 2.
Figure 2.
Inflammatory and host defense effector mechanisms driven by citrate, succinate, and glycolysis. The activation of macrophages with LPS leads to a broken Krebs cycle. This leads to inflammatory mediators (in red), where succinate accumulates and activates HIF1α, which promotes IL-1β transcription. LPS also promotes glycolysis in which the enzyme HK1 also activates the NLRP3 inflammasome to promote pro–IL-1β processing. Citrate accumulation leads to the generation of prostaglandins, NO, and ROS. In host defense, citrate generates itaconate, which has a direct antibacterial effect (in green) inhibiting the glyoxylate shunt in bacteria (demonstrated for Salmonella and Mycobacteria), which decreases their viability. The orphan nuclear receptor ERRα is a well-known regulator of energy metabolism and mitochondrial biogenesis and has been shown to directly induce A20, a potent inhibitor of TLR4 signaling.
Figure 3.
Figure 3.
Anabolic metabolism versus catabolic metabolism and the control of DC immunogenicity versus tolerogenicity. PRR agonists, cytokines, and nutrient and O2 levels can influence the balance of anabolic to catabolic metabolism, as shown. mTOR and AMPK are important regulators of this metabolic balance, and their activation states are highly responsive to a broad array of intracellular and extracellular signals. Glycolysis coupled to the tricarboxylic acid (TCA) cycle and citrate export from mitochondria supports an array of biosynthetic processes that are critical for DC activation. In contrast, autophagy and the oxidation of fatty acids and glutamine can create a state in which DCs are tolerogenic.

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