Regulation of macrophage function related to atherosclerosis development

Atherosclerosis has been identified as a chronic inflammatory disease resulting from interactions between immune cells and their microenvironment in the walls of susceptible arteries. Macrophages, critical players in innate immunity, participate in major events throughout all stages of atherosclerosis progression. Work in this dissertation is specifically interested in regulation of macrophage functions in the context of atherosclerosis. First, using bone marrow transplantation, we investigated how loss of eukaryotic elongation factor 2 kinase (eEF2K) activity affected atherosclerosis progression. Compared to mice transplanted with wild-type bone marrow, mice transplanted with bone marrow from eEF2K deficient mice had reduced atherosclerosis development after being fed with high-fat diet for 16 weeks. Impaired tumor necrosis factor-α release and subsequent adhesion molecule expression in the eEF2K inactive group may account for the reduction of atherosclerotic plaques. This finding suggested that the eEF2K inhibitor may be clinically useful to treat atherosclerosis. Second, we examined how oxLDL was involved in macrophage plasticity. We found that oxLDL polarized macrophages towards a novel subtype named MoL, which was characterized by high expression levels of heme oxygenase-1 and macrophage inhibitory cytokine-1. MoL cells are polarized, in part, through the activation of the PI3K/Akt pathway. MoL cells specifically up-regulates vascular cell adhesion molecule-1. This finding provided a more comprehensive view of macrophage plasticity in the context of atherosclerosis. Finally, we investigated signal transduction of ceramide 1-phosphate induced vascular endothelial growth factor release in macrophages. Using pharmaceutical inhibitors, we ruled out contributions of p38 MAPK and PKC-ζ signalling, and showed that the PI3K/Akt and MEK/ERK pathways were responsible for this process. Although we have no solid evidence to conclude on the mechanisms by which signals transduced from the outside of the cell to the inside, a rational hypothesis that this transduction requires ceramide 1-phosphate to be either embedded into, or actively transported through, the plasma membrane has been proposed. In summary, work in this dissertation contributes to our understanding of how macrophages functions are regulated by interacting with factors in the microenvironment. Results from this dissertation provide potential new avenues for discovery of novel therapeutic approaches to treat atherosclerosis.Medicine, Faculty ofMedicine, Department ofExperimental Medicine, Division ofGraduat