Transcriptional regulation of the macrophage spectrum

New technologies made it possible to study macrophages in the plaque in great detail. In chapter 2 an overview is given of the different macrophage populations present in the plaque.
By designing and using drugs that intervene in epigenetic processes, macrophages can be therapeutically influenced. In chapter 3 the current developments for targeting epigenetic processes in the treatment of atherosclerosis are discussed.
In chapter 4 the phenotype of macrophages from mice with diet-induced obesity (DIO) and type 2 diabetes (T2D), and of mice cured of obesity and T2D by dietary modification was characterized. Macrophages from obese and diabetic mice respond less to (mimicking) a bacterial infection.
Chapter 5 shows that histone methyltransferase DOT1L plays an important role in the inflammatory response and lipid metabolism of macrophages. This hyperinflammatory phenotype is also present in inflammatory macrophages in the atherosclerotic plaque of mice lacking DOT1L in their macrophages.
In chapter 6 we describe that lipid accumulation specifically suppresses IFN-β production and subsequent reactions in macrophages. Inhibition of the type-I IFN response also is present in the monocytes of untreated FH patients which disappeared after treatment with lipid-lowering therapeutics.
Preclinical studies show that LDL-C not only stimulates atherogenesis but also results in the production of inflammatory monocytes in the bone marrow. In chapter 7 we show that LDL-C is associated with circulating monocyte percentages. In patients with FH, we were able to establish a link between disturbed lipid homeostasis in bone marrow stem cells and atherosclerosis-stimulating changes in these stem cells.