ePoster Presentation 49th Annual Scientific Meeting of the Australian and New Zealand Society for Immunology 2021

The role of cellular energy metabolism in controlling indoleamine 2,3-dioxygenase 1 (IDO1) in human macrophages (#114)

Bentotage S.M Fernando 1 , Nicodemus Tedla 1 , Nicholas J.C King 2 , Shane R Thomas 1
  1. Mechanism of Disease and Translational Research, School of Medical Sciences, University of New South Wales , Sydney , New South Wales, Australia
  2. Discipline of Pathology, School Medical Sciences, Sydney Medical School, University of Sydney, Sydney, NSW, Australia

Cellular energy metabolism regulates macrophage immune function [1, 2]. Expression of the heme enzyme indoleamine 2,3-dioxygenase 1 (IDO1) in macrophages represents an important immunoregulatory mechanism signaling for immunosuppression during inflammation and cancer [3]. Here we examined the role of various metabolic pathways in controlling IDO1 in interferon-γ (IFNγ)- and lipopolysaccharide (LPS)-stimulated human monocyte-derived macrophages (MDMs). Inhibiting glycolysis with 2-deoxyglucose (2-DG) robustly inhibited IDO1 mRNA and protein expression, and enzyme activity in IFN-γ-stimulated MDMs, which correlated with the inhibition of STAT1 phosphorylation, which is essential for IDO1 transcription. Interestingly, LPS-stimulation inhibited IDO1 protein expression and enzyme activity without altering IDO1 mRNA levels, indicating post-transcriptional and/or translational control. Interfering with the metabolism of pyruvate (the terminal product of glycolysis) with the pyruvate analogue, oxamate and lactate dehydrogenase inhibitor, FX11 significantly inhibited IDO1 enzyme activity but not protein expression in IFNγ- or LPS-stimulated MDMs. Supplementation of Krebs Cycle metabolites, itaconate and succinate also inhibited IFNγ- and LPS-induced IDO1 activity. While itaconate-mediated inhibition was independent of changes to IDO1 protein, succinate reduced IDO1 protein in LPS- but not IFNγ-stimulated MDMs. Mitochondrial respiratory chain inhibitors with rotenone, carbonyl cyanide p-trifluoro-methoxyphenyl hydrazone (FCCP) or oligomycin and the mitochondrial-targeted antioxidant, mitoTEMPO, all inhibited IDO1 protein expression and activity in IFNγ- and LPS-stimulated MDMs. Inhibition of mitochondrial fatty acid oxidation with etomoxir (ETO), significantly inhibited IDO1 activity in IFNγ- or LPS-stimulated MDMs, without altering IDO1 protein levels.

Overall, our data suggest that IDO1 in MDMs is subject to transcriptional and/or post-translational control by several different pathways of cellular energy metabolism. This supports that the link between energy metabolism and macrophage immune function involves the regulation of IDO1.

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  3. Yeung, A.W., et al., Role of indoleamine 2,3-dioxygenase in health and disease. Clin Sci (Lond), 2015. 129(7): p. 601-72.