Metabolic reprogramming emerged as a crucial regulator of immune cell activation. However, how systemic metabolism influences immune cell metabolism and function remains to be investigated. During all stages of atherosclerosis foam cells, lipid-loaded macrophages, participate in disease progression. We hypothesized that metabolic changes in foam cells could underlie their phenotype.
To investigate the effect of foam cell formation on macrophage metabolism, we performed in-depth transcriptional, metabolic and functional characterization of peritoneal macrophages obtained from low-density lipoprotein receptor (Ldlr)-/- mice fed a high-fat diet (HFD).
Systemic metabolic changes in these mice translate into altered cellular macrophage metabolism and attenuates lipopolysaccharide (LPS)-induced expression of inflammatory genes, secretion of pro-inflammatory cytokines and nitric oxide (NO) production. Extracellular flux analyses and mass spectrometry demonstrated that this reduced inflammatory phenotype in foam cells is not accompanied with major changes in glycolysis or a reconfigured TCA cycle. Interestingly, LPS-elicited induction of pentose phosphate pathway (PPP) intermediates the Nrf2-mediated oxidative stress response were reduced upon foam cell formation. Pharmacological inhibition of the PPP showed the same diminished LPS-induced cytokine secretion and NO production. Next, to validate if the Nrf2-mediated oxidative stress pathway could act upstream of the PPP, we revealed a similar decreased expression of Pgd in Nrf2-deficient macrophages.  
In conclusion, this demonstrates a link between reduced Nrf2, a defective PPP and inflammatory response in HFD macrophages. Overall, this study reveals that foam cell formation and cellular metabolism are directly intertwined and together regulate macrophage function.

07 - A DEFECTIVE PENTOSE PHOSPHATE PATHWAY REDUCES INFLAMMATORY MACROPHAGE RESPONSES DURING HYPERCHOLESTEROLEMIA