Metabolic orchestration of macrophages in disease

Macrophages are essential components of our innate immune system and are able to ingest and destroy dangerous invaders. In addition to their pivotal role during host defense, macrophages exhibit great functional diversity and are involved in development, homeostasis and tissue repair. Nevertheless, perturbed macrophage responses are associated with collateral tissue damage and can drive disease progression, including atherosclerosis. Emerging evidence demonstrates that responses of macrophages are tightly intertwined with their intracellular metabolism. This thesis provides novel insights into the interplay between metabolism and macrophage function. We show that inflammatory (M1) macrophage activation is accompanied by irreversible alterations in the mitochondria, preventing the repolarization to an anti-inflammatory (M2) macrophage. Moreover, we reveal in this thesis that hypercholesterolemia, one of the most prominent risk factors for developing atherosclerosis, suppresses the pentose phosphate pathway in macrophages, together with attenuated M1 responses. Furthermore, we demonstrate that loss of the metabolic enzyme ATP citrate lyase (Acly) in macrophages blunts their M2 responses. Additionally, we show that macrophage-specific deletion of Acly stabilizes the progression of atherosclerosis.