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

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, HIF1a, 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. (c) 2021 The Author(s). Published by Elsevier GmbH. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

Automated summary

This study reveals that glucocorticoids control macrophage metabolism by repressing glycolysis and promoting the tricarboxylic acid cycle flux, leading to anti-inflammatory effects. The transcription factor HIF1a is identified as a key regulator of glucocorticoid responsiveness during inflammatory challenge.