Immunometabolism in the Brain: How Metabolism Shapes Microglial Function

Bernier, Louis‐Philippe; York, Elisa M.; MacVicar, Brian A.

doi:10.1016/j.tins.2020.08.008

Cited by 125 publications

(110 citation statements)

References 149 publications

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“…On basis of transcriptome studies, it was suggested that microglia express all enzymes necessary to cover the major metabolic pathways [21,60]. Indeed, the bioenergetic microglia machinery is able to utilize glucose, glutamine, pyruvate, lactate, ketone bodies, or fatty acids as energy substrates [16,59,61]. Recent in vivo studies revealed metabolic flexibility of microglia that, under glucose deprived conditions, can switch to glutaminolysis in an mTOR-dependent manner [16,20].…”

Section: Discussionmentioning

confidence: 99%

“…Indeed, the bioenergetic microglia machinery is able to utilize glucose, glutamine, pyruvate, lactate, ketone bodies, or fatty acids as energy substrates [16,59,61]. Recent in vivo studies revealed metabolic flexibility of microglia that, under glucose deprived conditions, can switch to glutaminolysis in an mTOR-dependent manner [16,20]. All of these pathways converge on oxidative metabolism in mitochondria under physiological conditions.…”

Section: Discussionmentioning

confidence: 99%

“…The transient metabolic profile of immune cells has profound implications on the induction of pro-or anti-inflammatory phenotypes [16,17]. Within the field of immunometabolism several aspects of metabolic pathway utilization/adaption and the resulting immune cell phenotype in the periphery are clarified, however, this field is just emerging in microglia biology [16,18]. Transcriptomic studies indicate that microglia express transporters for glucose, glutamine, and fatty acids (FA) and like macrophages, microglia display metabolic flexibility and are able to rewire energy fuel utilization [19].…”

Section: Introductionmentioning

confidence: 99%

“…Transcriptomic studies indicate that microglia express transporters for glucose, glutamine, and fatty acids (FA) and like macrophages, microglia display metabolic flexibility and are able to rewire energy fuel utilization [19]. In the absence of glucose microglia are able to consume glutamine as an alternative nutrient source, while the contribution of β-oxidation to cellular energy homeostasis generation is not entirely clear [16,20]. To get an indication about basic metabolic pathway utilization of microglia some of these studies were performed in "unstimulated" cells resembling microglia in their surveillance state [21,22].…”

Section: Introductionmentioning

confidence: 99%

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Lysophosphatidic Acid Induces Aerobic Glycolysis, Lipogenesis, and Increased Amino Acid Uptake in BV-2 Microglia

Joshi

Plastira

Bernhart

et al. 2021

IJMS

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Lysophosphatidic acid (LPA) species are a family of bioactive lipids that transmit signals via six cognate G protein-coupled receptors, which are required for brain development and function of the nervous system. LPA affects the function of all cell types in the brain and can display beneficial or detrimental effects on microglia function. During earlier studies we reported that LPA treatment of microglia induces polarization towards a neurotoxic phenotype. In the present study we investigated whether these alterations are accompanied by the induction of a specific immunometabolic phenotype in LPA-treated BV-2 microglia. In response to LPA (1 µM) we observed slightly decreased mitochondrial respiration, increased lactate secretion and reduced ATP/ADP ratios indicating a switch towards aerobic glycolysis. Pathway analyses demonstrated induction of the Akt-mTOR-Hif1α axis under normoxic conditions. LPA treatment resulted in dephosphorylation of AMP-activated kinase, de-repression of acetyl-CoA-carboxylase and increased fatty acid content in the phospholipid and triacylglycerol fraction of BV-2 microglia lipid extracts, indicating de novo lipogenesis. LPA led to increased intracellular amino acid content at one or more time points. Finally, we observed LPA-dependent generation of reactive oxygen species (ROS), phosphorylation of nuclear factor erythroid 2–related factor 2 (Nrf2), upregulated protein expression of the Nrf2 target regulatory subunit of glutamate-cysteine ligase and increased glutathione synthesis. Our observations suggest that LPA, as a bioactive lipid, induces subtle alterations of the immunometabolic program in BV-2 microglia.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Lysophosphatidic Acid Induces Aerobic Glycolysis, Lipogenesis, and Increased Amino Acid Uptake in BV-2 Microglia

Joshi

Plastira

Bernhart

et al. 2021

IJMS

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show abstract

“…Similar to macrophages 6,7 , microglia exposed to proinflammatory stimulus shift their metabolism from oxidative phosphorylation (OXPHOS) to aerobic glycolysis 9,10 , in an event similar to the Warburg effect suffered by cancer cells 7 . This metabolic reprogramming is essential to activate cellular defense mechanisms and to manage various microenvironments in inflamed tissue 7,[11][12][13] .…”

Section: Introductionmentioning

confidence: 99%

Role of Mitochondrial Dynamics in Microglial Activation and Metabolic Switch

Montilla

Ruiz

Márquez

et al. 2021

Preprint

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Microglia act as sensors of injury in the brain, favouring its homeostasis. Their activation and polarization towards a pro-inflammatory phenotype are associated to injury and disease. These processes are linked to a metabolic reprogramming of the cells, characterized by high rates of glycolysis and suppressed oxidative phosphorylation. This metabolic switch can be reproduced in vitro by microglial stimulation with lipopolysaccharide (LPS) plus interferon-γ (IFNγ). In order to understand the mechanisms regulating mitochondrial respiration abolishment, we examined potential alterations in mitochondrial features during this switch. Cells did not show any change in mitochondrial membrane potential, suggesting a limited impact in the mitochondrial viability. We provide evidence that reverse operation of F0F1-ATP synthase contributes to mitochondrial membrane potential. In addition, we studied the possible implication of mitochondrial dynamics in the metabolic switch using the mitochondrial division inhibitor-1 (Mdivi-1), which blocks Drp1-dependent mitochondrial fission. Mdivi-1 significantly reduced the expression of pro-inflammatory markers in LPS+IFNγ-treated microglia. However, this inhibition did not lead to a recovery of the oxidative phosphorylation ablation by LPS+IFNγ or to a microglia repolarization. Altogether, these results suggest that Drp1-dependent mitochondrial fission, although potentially involved in microglial activation, does not play an essential role in metabolic reprogramming and repolarization of microglia.

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Biomimetic Remodeling of Microglial Riboflavin Metabolism Ameliorates Cognitive Impairment by Modulating Neuroinflammation

et al. 2023

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Neuroinflammation, for which microglia are the predominant contributors, is a significant risk factor for cognitive dysfunction. Riboflavin (also known as vitamin B2) ameliorates cognitive impairment via anti‐oxidative stress and anti‐inflammation properties; however, the underlying mechanisms linking riboflavin metabolism and microglial function in cognitive impairment remain unclear. Here, it is demonstrated that riboflavin kinase (RFK), a critical enzyme in riboflavin metabolism, is specifically expressed in microglia. An intermediate product of riboflavin, flavin mononucleotide (FMN), inhibited RFK expression via regulation of lysine‐specific methyltransferase 2B (KMT2B). FMN supplementation attenuated the pro‐inflammatory TNFR1/NF‐κB signaling pathway, and this effect is abolished by KMT2B overexpression. To improve the limited anti‐inflammatory efficiency of free FMN, a biomimetic microglial nanoparticle strategy (designated as MNPs@FMN) is established, which penetrated the blood brain barrier with enhanced microglial‐targeted delivery efficiency. Notably, MNPs@FMN ameliorated cognitive impairment and dysfunctional synaptic plasticity in a lipopolysaccharide‐induced inflammatory mouse model and in a 5xFAD mouse model of Alzheimer's disease. Taken together, biomimetic microglial delivery of FMN may serve as a potential therapeutic approach for inflammation‐dependent cognitive decline.

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Immunometabolism in the Brain: How Metabolism Shapes Microglial Function

Cited by 125 publications

References 149 publications

Lysophosphatidic Acid Induces Aerobic Glycolysis, Lipogenesis, and Increased Amino Acid Uptake in BV-2 Microglia

Lysophosphatidic Acid Induces Aerobic Glycolysis, Lipogenesis, and Increased Amino Acid Uptake in BV-2 Microglia

Role of Mitochondrial Dynamics in Microglial Activation and Metabolic Switch

Biomimetic Remodeling of Microglial Riboflavin Metabolism Ameliorates Cognitive Impairment by Modulating Neuroinflammation

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