Pentose Phosphate Pathway Activation in Atherosclerosis

Metabolic syndrome, which is associated with insulin resistance and hyperglycaemic states, is an important risk factor for atherosclerosis. Recent research in immunology indicates that t he activation of immune cells is mechanistically linked to reprogramming of cellular metabolism. In this interdisciplinary project, we will investigate how and under what conditions glucose metabolism of immune cells, particularly via the pentose phosphate pathway, influence their cellular function in the development and progression of atherosclerosis. We will focus on the expansion and activation of myeloid cells in atherosclerotic plaques and aim to gain a better understanding of cardiovascular diseases, taking account of the relationship between energy metabolism, immune cell activation and the formation of atherosclerotic plaques.

Metabolic syndrome, which is associated with insulin resistance and hyperglycemic states, is an important risk factor for atherosclerosis. Recent research in immunology indicates that the activation of immune cells is mechanistically linked to reprogramming of cellular metabolism. In this interdisciplinary project, we investigated how and under what conditions glucose metabolism of immune cells, particularly via the pentose phosphate pathway (PPP), influence their cellular function in the development and progression of atherosclerosis. We focused on the expansion and activation of myeloid cells in atherosclerotic plaques and aimed to gain a better understanding of cardiovascular diseases, considering the relationships between energy metabolism, immune cell activation and the formation of atherosclerotic plaques. Our studies revealed that glucose metabolism controls monocyte behavior in blood and peripheral tissues during atherosclerosis progression. Blocking glucose uptake systemically diminished blood and spleen monocyte counts, while the remaining monocytes showed improved migratory capacity. However, systemically administered pharmacological inhibitors of glucose uptake, glycolysis and the PPP showed only minor impact on plaque progression in an interventional study using preclinical disease models. In order to selectively define to role of intracellular metabolic cues specifically in myeloid cell on plaque development, we genetically targeted important metabolic regulators of glycolysis and the PPP. Targeting an inducer of glycolysis in macrophages did not affect plaque progression, suggesting that enhanced glycolysis is not a critical determinant in atherosclerosis development. However, targeting the PPP genetically in myeloid cells reduced lipid depositions and plaque development, and additionally revealed an altered plaque composition, which defines plaque stability and thereby the risk of rupture. Our data indicates that perturbation of PPP activity in macrophages significantly impacts their activation states and effector functions relevant for plaque formation. This included their ability to scavenge excessive lipids and secrete cytokines as well as their phagocytic capacity, which together form core processes important for atherosclerotic plaque development and progression. Moreover, we investigated metabolic signatures of cells directly within the atherosclerotic plaque. We found increased PPP enzyme activities enriched in macrophages at specific localizations within the atherosclerotic plaque microenvironment, which further suggested that in myeloid cells this particular metabolic pathway plays an important role in disease development. In additional studies, we also revealed novel molecular interfaces important for regulating the cross-talk of cellular metabolism and immune cell functions in macrophages, providing a more profound understanding of the underlying "immune-metabolic" mechanisms in place. In summary, we conclude from our studies that glucose uptake is particularly important for monocyte homeostasis, while cell intrinsic PPP activity in macrophages is key for their effector functions relevant for atherosclerotic plaque development. Moreover, our studies revealed a complex interplay of metabolic pathways with immune cell functions, and ultimately with disease development.