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Review
. 2018 Jun;19(6):526-537.
doi: 10.1038/s41590-018-0113-3. Epub 2018 May 18.

Regulation of macrophage immunometabolism in atherosclerosis

Graeme J Koelwyn  1 , Emma M Corr  1 , Ebru Erbay  2   3   4 , Kathryn J Moore  5
Affiliations
Review

Regulation of macrophage immunometabolism in atherosclerosis

Graeme J Koelwyn et al. Nat Immunol. 2018 Jun.

Abstract

After activation, cells of the myeloid lineage undergo robust metabolic transitions, as well as discrete epigenetic changes, that can dictate both ongoing and future inflammatory responses. In atherosclerosis, in which macrophages play central roles in the initiation, growth, and ultimately rupture of arterial plaques, altered metabolism is a key feature that dictates macrophage function and subsequent disease progression. This Review explores how factors central to the plaque microenvironment (for example, altered cholesterol metabolism, oxidative stress, hypoxia, apoptotic and necrotic cells, and hyperglycemia) shape the metabolic rewiring of macrophages in atherosclerosis as well as how these metabolic shifts in turn alter macrophage immune-effector and tissue-reparative functions. Finally, this overview offers insight into the challenges and opportunities of harnessing metabolism to modulate aberrant macrophage responses in disease.

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Figures

Figure 1.
Figure 1.. Metabolic pathways controlling macrophage activation states
Glycolysis involves the conversion of glucose molecules into various metabolic byproducts, culminating in the end product pyruvate as well as 2 net ATP. In macrophages treated with interleukin (IL)-4, (M[IL-4], left side of the cell) pyruvate (and fatty acids) enters the intact tricarboxylic acid (TCA) cycle, as acetyl coenzyme A (Acetyl-CoA), resulting in sustained ATP production via oxidative phosphorylation (OXPHOS) and leading to the upregulation of genes associated with tissue repair. Conversely, in macrophages treated with lipopolysaccharide (LPS) and interferon-gamma (IFN-γ) (M[LPS+IFN-γ] right side of the cell) the majority of pyruvate is converted into lactate and secreted. Furthermore, the enzyme carbohydrate kinase-like protein (CARKL) is downregulated, and as a result, glycolysis also feeds the pentose phosphate pathway (PPP) generating nucleotides, amino acids and NADPH. The TCA cycle is broken in two places in M[LPS+IFN-γ] macrophages resulting in the accumulation of citrate that is used to drive fatty acid synthesis (FAS) and succinate that stabilizes the transcription factor hypoxia-inducible factor-1-alpha (HIF-1α). HIF-1α enters the nucleus and promotes the expression of hypoxia response element (HRE) containing genes, which include both glycolytic and pro-inflammatory genes such as interleukin-1beta (IL-1β). The disturbed TCA cycle and reduced oxidative phosphorylation (OXPHOS) also result in increased levels of reactive oxygen species (ROS), which further stabilize HIF-1α to drive glycolysis and inflammatory gene expression. Glut-1, glucose transporter-1; G6P, glucose-6-phosphate; F6P, fructose-6-phosphate; OAA, oxaloacetate; NADPH, Nicotinamide adenine dinucleotide phosphate.
Figure 2.
Figure 2.. Macrophage Metabolic reprogramming in the atherosclerotic plaque
Prior to recruitment to the atherosclerotic plaque, monocytes exhibit a ‘primed’ inflammatory phenotype, characterized by enhanced inflammatory responses that correspond to increases in both glycolysis and oxidative phosphorylation. Within the plaque microenvironment, a variety of stimuli including lipids, cytokines, cell apoptosis and necrosis, hypoxia, and hyperglycemia can all regulate macrophage metabolic reprogramming and subsequent function. Distinct macrophage phenotypes have been identified within the plaque, including M[IL-4]-like, M(Ox), M[LPS+IFNg]-like, and hypoxia-associated macrophages. These different flavors of macrophages are each associated with distinct metabolic signatures and inflammatory functions. PPP, pentose phosphate pathway; FAO, fatty acid oxidation; TCA, tricarboxylic acid cycle, OXPHOS, oxidative phosphorylation; GLUT-1, glucose transporter-1; HIF-1α, hypoxia-inducible factor-1-alpha; PPARγ, Peroxisome proliferator-activated receptor gamma; NRF2, nuclear factor 2
Figure 3.
Figure 3.. Epigenetic alterations that shape the macrophage immune response
Stimuli that activate immune cells and induce metabolic rewiring are also capable of inducing epigenetic remodeling, through histone modifications, which results in innate immune memory. Histone modifications, including methylation and acetylation of specific residues within promotor regions of genes, which occur via the activity of histone-modifying enzymes, determine chromatin structure and enable transcription factor recruitment. The effect of methylation on transcription depends on the targeted residue and the degree of methylation; for example, trimethylation of histone H3 at lysine-4 (H3K4me3) is associated with transcriptional activation, whereas trimethylation of histone H3 at lysine-27 (H3K27me3) is linked with gene repression. Acetylation on lysine residues leads to a more open accessible chromatin state and is associated with gene expression. In trained macrophages (A) (i.e. those stimulated with BCG or β-glucan), a broken tricarboxylic acid (TCA) cycle results in the accumulation of citrate and succinate. These metabolites activate histone-modifying enzymes, such as histone acetyl transferase, which leads to an increase in H3K4me3 and acetylation of histone H3 at lysine-27 (H3K27Ac) at promoter sites of inflammatory cytokine genes and subsequently results in an increased inflammatory response. Additionally, a decreased nicotinamide adenine dinucleotide (NAD+) to NAD plus hydrogen (NADH) ratio in trained cells inhibits the activity of NAD+-dependent histone deacetylase sirtuin-1 and −6 supporting the increased inflammatory response. This response is absent in non-trained macrophages (B), which have lower basal levels of H3K4me3 and H3K27Ac due to an intact TCA cycle (preventing the accumulation of citrate and succinate), and an increased NAD+/NADH ratio which activates histone deacetylase sirtuin-1 and sirtuin-6. OXPHOS, oxidative phosphorylation; Glut-1, glucose transporter-1; Acetyl-CoA, acetyl-coenzyme A; HIF-1α, hypoxia-inducible factor-1-alpha; Akt; protein kinase B.
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