Immunometabolism in monocytes and macrophages during inflammation and pneumonia

The aim of this thesis is to investigate the role of glucose metabolism in the immune response of monocytes and macrophages during activation and infection (during pneumonia and pneumosepsis). In chapter 2 and 3, we assessed the role of two key mediators in glucose metabolism, LKB1 and HIF1α, in the function of myeloid cells, especially alveolar macrophages, during K. pneumoniae-induced pneumonia and pneumosepsis. LKB1 seems important for the number of alveolar macrophages and therefore host defense. HIF1α depletion affects the TNF production of these cells. In chapter 4, we repurposed transcriptomic analysis to determine the immunometabolic pathways important for human alveolar macrophage activation by LPS. In this and the previous chapters we provide evidence for the finding that murine and human alveolar macrophages do not induce glycolysis upon activation. The effect of HIF1α-stabilization on stimulated monocytes and macrophages is described in chapter 5. Here we show that human monocytes respond differently to this than macrophages. Chapter 6 is dedicated to the effect of adherence on the function and metabolic changes that occur in activated monocytes. We found that adherent monocytes were more anti-inflammatory but induced glycolysis upon stimulation. While nonadherent monocytes produced more inflammatory cytokines, they did not induce glycolysis upon stimulation. The metabolic adaptation of circulating monocytes from patients with pneumonia are described in chapter 7. Here we show that monocytes from pneumonia-patients contain more intracellular pyruvate and α-ketoglutarate and that intracellular pyruvate levels correlate with the cytokine production capacity of these cells.