| Summary: | <p>Macrophages are highly heterogeneous, plastic immune cells that perform a diverse spectrum of functions. Defined by their metabolic signature, macrophages stimulated by LPS/IFN-γ (M<sup>LPS/IFN-γ</sup>) display reduced oxidative phosphorylation, due to breaks in the TCA cycle, switching instead to glycolysis to meet their energy requirements. Through targeted modulation of this glycolytic switch, and modulating macrophage metabolism generally, there is potential to alter macrophage function and impact their role in the development of cardiovascular diseases.</p>
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<p>Previously, our group has shown that tetrahydrobiopterin (BH4) alters mitochondrial respiration in M<sup>LPS/IFN-γ</sup> macrophages. A newly generated model of BH4 deficiency revealed that BH4 is required for the TCA cycle breaks to completely occur resulting in downregulation of glycolysis, and increased reliance on OXPHOS, due to glutaminolysis supplementation in BH4-deficient M<sup>LPS/IFN-γ</sup> macrophages. These BH4-deficient M<sup>LPS/IFN-γ</sup> macrophages exhibited a less inflammatory phenotype due to decreased levels of proinflammatory metabolites such as eicosanoids, and increased levels of anti-inflammatory metabolites, such as itaconate, which was also discovered to be secreted from macrophages in large quantities. Itaconate was used as a marker of inflammation throughout the study. <em>ACOD1</em>, encoding CAD enzyme which produces itaconate, minor allele rs17470171 was associated with altered redox state and improved vascular function in patients with cardiovascular disease. Following on, itaconate treatment caused loss of constriction in mouse aortas via endothelial independent mechanisms. This study proposes a non-immune
related role for itaconate, adding to the evidence for a therapeutic role for itaconate.</p>
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<p>In addition, the study investigated the impact of hyperglycaemia as an inflammatory and metabolic stimulus in M<sup>LPS/IFN-γ</sup>. In vitro high glucose treatment did not yield alterations in the inflammatory or metabolic profile of macrophages but in vivo hyperglycaemia primed M<sup>LPS/IFN-γ</sup> to have altered proinflammatory cytokine release. Metabolomics analysis revealed increased levels of glycolytic metabolites and sphingomyelins following secondary stimulus in diabetic M<sup>LPS/IFN-γ</sup> macrophages. The majority of other metabolic pathways and inflammatory metabolites remained unchanged, including itaconate. Further studies are required to determine if these metabolic changes translate into functional outcomes.</p>
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<p>Overall, the study demonstrates altering cell bioenergetics, via BH4 loss or hyperglycaemia, can be a viable approach to modifying macrophage phenotype. Additionally, itaconate has potential non-immune related roles that need to be further explored but are promising treatments for cardiovascular or inflammatory diseases.</p>
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