Metabolic support of trained immune responses in myeloid cells
- Immunobiology Laboratory, Centro Nacional de Investigaciones Cardiovasculares CNIC, Spain
- Escuela de Doctorado, Universidad Autónoma de Madrid, Spain
- Department of Molecular Cell Biology and Immunology, Amsterdam Institute for Immunology and Infectious Diseases, Amsterdam Cardiovascular Sciences, Amsterdam UMC, Vrije Universiteit Amsterdam, Netherlands
Figures
Figure 1
Cellular metabolites control epigenetic modifications during trained immunity (TI) induction.
Main metabolic pathways, depicted with a maroon background, involved in TI induction through epigenetic modifications in both the mitochondria (red background) and the cytosol (blue background). Metabolic directions of metabolites are represented with black arrows, while blue arrows show the crosstalk between specific metabolites and epigenetic modifications. TCA cycle metabolites like α-ketoglutarate (αKG), succinate, and fumarate affect enzymatic activity of histone and DNA demethylases. S-adenosylmethionine (SAM), produced in the methionine cycle, promotes histone and DNA methylation. Citrate-derived acetyl-CoA is required for histone acetylation, while NAD+ is a cofactor required for sirtuin histone deacetylases (HDACs). Lactate promotes histone lactylation, which works in a similar way as histone acetylation, loosening chromatin structure and activating gene transcription. Epigenetic modifications are shown in the nucleus (purple background). DNA methyltransferases (DNMTs) and ten-eleven-translocation (TET) proteins are involved in DNA methylation and demethylation, respectively. Histone acetyltransferases (HATs), like p300, and HDACs, trigger histone acetylation/lactylation and deacetylation/delactylation, respectively. Histone lysine methyltransferases (KMTs) and histone lysine demethylases (KDMs) are involved in methyl transfer from SAM to histone lysine residues and its removal, respectively. LDH, lactate dehydrogenase; ACLY, ATP citrate lyase; PDH, pyruvate dehydrogenase; NAD+, nicotinamide adenine dinucleotide; NADH, nicotinamide adenine dinucleotide reduced; 2-HG, 2-hydroxyglutarate; TF, transcription factors; SAM, S-adenosylmethionine; PAMP, pathogen-associated molecular pattern; DAMP, damage-associated molecular pattern.
Figure 2
Metabolic adaptations improve immune function in trained cells.
Upon myeloid cell detection of training stimuli, such as β-glucan by the receptor Dectin-1, a wide array of metabolic changes take place in the cell. The activation of mTOR is essential for trained immunity (TI) induction. Two of the main effects of this activation are increased protein translation and increased glycolysis. Protein translation can support inflammatory cytokines, as well as components of other cellular processes to enhance cellular function. Glycolysis begins with the conversion of glucose to glucose-6-phosphate (G6P) by the enzyme HK1 and finishes with the generation of pyruvate. G6P can also be utilised in the oxidative PPP to generate R5P required for nucleotide synthesis and NADPH. NADPH is used by NOX to generate ROS. While ROS can be used in several immune responses, in the context of TI, ROS was shown to inhibit mTOR activation and decrease cytokine production. The other role of NADPH is the reduction of glutathione, and subsequent antioxidant function, this allows mTOR activation and promotes cell survival. Further glycolysis metabolites F6P and G3P can also contribute to R5P generation by non-oxidative PPP. The glycolytic metabolite 3PG can be diverted to de novo serine synthesis, a pathway that generates NADH and α-ketoglutarate (αKG), as well as serine and glycine. At the end of glycolysis, pyruvate can be converted to lactate in the cytoplasm, or to acetyl-CoA in the mitochondria to fuel the TCA cycle. In the mitochondria, acetyl-CoA is converted to citrate, which can be exported to the cytoplasm where it fuels FA synthesis and cholesterol synthesis pathways. FAs can also be imported directly into the cytoplasm. Increased intracellular lipid species support the expansion of cell membranes and the production of inflammatory mediators. As well as production of the end product cholesterol, this pathway also generates the intermediate product Mevalonate, which was shown to bind to the receptor IGF1R in an autocrine manner, activating mTOR. Citrate can also be maintained in the mitochondria to continue the TCA cycle. The enzyme IDH3, which results in the generation of αKG, was downregulated by the miRNA miR-9-5p, resulting in decreased αKG levels. This decreases the proportion of αKG to succinate and fumarate, promoting stabilisation of HIF1α, which can then translocate to the nucleus where it acts as a TF to promote glycolysis and inflammatory gene expression. Succinate is converted to fumarate by succinate dehydrogenase (SDH), the expression of which is increased in trained cells. SDH also participates in the ETC as Complex II, contributing to the generation of mitochondrial ATP. The TCA cycle enzyme MDH was also found to be transcriptionally increased, metabolising malate to continue the flow of the TCA cycle. mTOR, mammalian target of Rapamycin; G6P, glucose-6-phosphate; F6P, fructose-6-phosphate; G3P, glyceraldehyde-3-phosphate; 3PG, 3-phosphoglycerate; PPP, pentose phosphate pathway; 6PG, 6-phosphogluconate; R5P, ribose 5-phosphate; NOX, NADPH oxidase; ROS, reactive oxygen species; GSSG, glutathione disulfide; GSH, glutathione; NADPH, nicotinamide adenine dinucleotide phosphate (reduced form); NADP+, nicotinamide adenine dinucleotide phosphate (oxidized form); NADH, nicotinamide adenine dinucleotide (reduced form); NAD+, nicotinamide adenine dinucleotide (oxidized form); 3PHP, 3-phosphohydroxypyruvate; 3PS, 3-phosphoserine; IGF1R, insulin-like growth factor 1 receptor; TCA, tricarboxylic acid; MDH, malate dehydrogenase; SDH, succinate dehydrogenase; IDH3α, isocitrate dehydrogenase (NAD(+)) 3 catalytic subunit alpha; Glu, glutamate; αKG, alpha ketoglutarate; FA, fatty acid; CoA, coenzyme A; ETC, electron transport chain; ATP, adenosine triphosphate; HIF1a, hypoxia inducible factor 1 subunit alpha, mRNA, messenger RNA; miRNA, micro RNA.
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Metabolic support of trained immune responses in myeloid cells
eLife 15:e108814.
https://doi.org/10.7554/eLife.108814
