Dataset Information

Glucocorticoids coordinate macrophage metabolism through the regulation of the tricarboxylic acid cycle.

ABSTRACT:

Objectives

Glucocorticoids (GCs) are one of the most widely prescribed anti-inflammatory drugs. By acting through their cognate receptor, the glucocorticoid receptor (GR), GCs downregulate the expression of pro-inflammatory genes and upregulate the expression of anti-inflammatory genes. Metabolic pathways have recently been identified as key parts of both the inflammatory activation and anti-inflammatory polarization of macrophages, immune cells responsible for acute inflammation and tissue repair. It is currently unknown whether GCs control macrophage metabolism, and if so, to what extent metabolic regulation by GCs confers anti-inflammatory activity.

Methods

Using transcriptomic and metabolomic profiling of macrophages, we identified GC-controlled pathways involved in metabolism, especially in mitochondrial function.

Results

Metabolic analyses revealed that GCs repress glycolysis in inflammatory myeloid cells and promote tricarboxylic acid (TCA) cycle flux, promoting succinate metabolism and preventing intracellular accumulation of succinate. Inhibition of ATP synthase attenuated GC-induced transcriptional changes, likely through stalling of TCA cycle anaplerosis. We further identified a glycolytic regulatory transcription factor, HIF1α, as regulated by GCs, and as a key regulator of GC responsiveness during inflammatory challenge.

Conclusions

Our findings link metabolism to gene regulation by GCs in macrophages.

SUBMITTER: Stifel U

PROVIDER: S-EPMC8783148 | biostudies-literature | 2021 Dec

REPOSITORIES: biostudies-literature

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Publications

Glucocorticoids coordinate macrophage metabolism through the regulation of the tricarboxylic acid cycle.

Stifel Ulrich U Wolfschmitt Eva-Maria EM Vogt Josef J Wachter Ulrich U Vettorazzi Sabine S Tews Daniel D Hogg Melanie M Zink Fabian F Koll Nora Maria NM Winning Sandra S Mounier Rémi R Chazaud Bénédicte B Radermacher Peter P Fischer-Posovszky Pamela P Caratti Giorgio G Tuckermann Jan J

Molecular metabolism 20211222

<h4>Objectives</h4>Glucocorticoids (GCs) are one of the most widely prescribed anti-inflammatory drugs. By acting through their cognate receptor, the glucocorticoid receptor (GR), GCs downregulate the expression of pro-inflammatory genes and upregulate the expression of anti-inflammatory genes. Metabolic pathways have recently been identified as key parts of both the inflammatory activation and anti-inflammatory polarization of macrophages, immune cells responsible for acute inflammation and tis ...[more]

PMID: 34954109

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Project description:The coordination of metabolism and growth with cell division is crucial for proliferation. While it has long been known that cell metabolism regulates the cell division cycle, it is becoming increasingly clear that the cell division cycle also regulates metabolism. In budding yeast, we previously showed that over half of all measured metabolites change concentration through the cell cycle indicating that metabolic fluxes are extensively regulated during cell cycle progression. However, how this regulation is achieved still remains poorly understood. Since both the cell cycle and metabolism are regulated to a large extent by protein phosphorylation, we here decided to measure the phosphoproteome through the budding yeast cell cycle. Specifically, we chose a cell cycle synchronization strategy that avoids stress and nutrient-related perturbations of metabolism, and we grew the yeast on ethanol minimal medium to force cells to utilize their full biosynthetic repertoire. Using a tandem-mass-tagging approach, we found over 200 sites on metabolic enzymes and transporters to be phospho-regulated. These sites were distributed among many pathways including carbohydrate catabolism, lipid metabolism, and amino acid synthesis and therefore likely contribute to changing metabolic fluxes through the cell cycle. Among all one thousand sites whose phosphorylation increases through the cell cycle, the CDK consensus motif and an arginine-directed motif were highly enriched. This arginine-directed R-R-x-S motif is associated with protein-kinase A, which regulates metabolism and promotes growth. Finally, we also found over one thousand sites that are dephosphorylated through the G1/S transition. We speculate that the phosphatase Glc7/PP1, known to regulate both the cell cycle and carbon metabolism, may play an important role because its regulatory subunits are phospho-regulated in our data. In summary, our results identify extensive cell cycle dependent phosphorylation and dephosphorylation of metabolic enzymes and suggest multiple mechanisms through which the cell division cycle regulates metabolic signaling pathways to temporally coordinate biosynthesis with distinct phases of the cell division cycle.

Dataset Information

Glucocorticoids coordinate macrophage metabolism through the regulation of the tricarboxylic acid cycle.

Objectives

Methods

Results

Conclusions

Publications

Glucocorticoids coordinate macrophage metabolism through the regulation of the tricarboxylic acid cycle.

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