Abstract
Metabolism in immune cells is no longer thought of as merely a process for adenosine triphosphate (ATP) production, biosynthesis, and catabolism. The reprogramming of metabolic pathways upon activation is also for the production of metabolites that can act as immune signaling molecules. Activated dendritic cells (DCs) and macrophages have an altered Krebs cycle, one consequence of which is the accumulation of both citrate and succinate. Citrate is exported from the mitochondria via the mitochondrial citrate- carrier. Cytosolic metabolism of citrate to acetyl-coenzyme A (acetyl-CoA) is important for both fatty-acid synthesis and protein acetylation, both of which have been linked to macrophage and DC activation. Citrate-derived itaconate has a direct antibacterial effect and also has been shown to act as an anti-inflammatory agent, inhibiting succinate dehydrogenase. These findings identify citrate as an important metabolite for macrophage and DC effector function.
Highlights
Frontiers in ImmunologyCitrate-derived itaconate has a direct antibacterial effect and has been shown to act as an anti-inflammatory agent, inhibiting succinate dehydrogenase
Citrate-derived itaconate has a direct antibacterial effect and has been shown to act as an anti-inflammatory agent, inhibiting succinate dehydrogenase. These findings identify citrate as an important metabolite for macrophage and dendritic cell (DC) effector function
While the effects of studies carried out utilizing Dimethyl itaconate (DMI) have been drawn into question, the body of work carried out using genetic inhibition or deletion of immunoresponsive gene 1 (Irg1) and the striking amount by which Irg1 mRNA and itaconate synthesis are upregulated in activated immune cells still leaves it worthy of further investigation
Summary
Citrate-derived itaconate has a direct antibacterial effect and has been shown to act as an anti-inflammatory agent, inhibiting succinate dehydrogenase These findings identify citrate as an important metabolite for macrophage and DC effector function. A second breakpoint, at isocitrate dehydrogenase (IDH), allows for the withdrawal of citrate from the cycle This proves to be important for lipid biosynthesis in macrophages and DCs, and for the production of both pro- and anti-inflammatory mediators [32, 33]. Glycolysis is rapidly upregulated in LPS-activated DCs for the production of citrate This is necessary for the upregulation of fatty acid synthesis to allow for membrane expansion which is crucial for antigen presentation [34].
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