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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.

Lactulose, a non-digestible oligosaccharide and functional food, promotes Bifidobacteria growth. Here we show that lactulose, beyond its prebiotic action, may have direct immunomodulatory effects as well. In synergy with CpG-ODN, a bacterial DNA mimetic, lactulose enhances basolateral concentrations of IFN-γ, IL-10, and galectin-9 in the co-culture model of epithelial and immune cells.

PURPOSE: The incidence and severity of allergic asthma is rising, and novel strategies to prevent or treat this disease are needed. This study investigated the effects of different mixtures of non-digestible oligosaccharides combined with Bifidobacterium breve M-16V (BB) on the development of allergic airway inflammation in an animal model for house dust mite (HDM)-induced allergic asthma. METHODS: BALB/c mice were sensitized intranasally (i.n.) with HDM and subsequently challenged (i.n.) with PBS or HDM while being fed diets containing different oligosaccharide mixtures in combination with BB or an isocaloric identical control diet. Bronchoalveolar lavage fluid (BALF) inflammatory cell influx, chemokine and cytokine concentrations in lung homogenates and supernatants of ex vivo HDM-restimulated lung cells were analyzed. RESULTS: The HDM-induced influx of eosinophils and lymphocytes was reduced by the diet containing the short-chain and long-chain fructo-oligosaccharides and BB (FFBB). In addition to the HDM-induced cell influx, concentrations of IL-33, CCL17, CCL22, IL-6, IL-13 and IL-5 were increased in supernatants of lung homogenates or BALF and IL-4, IFN-γ and IL-10 were increased in restimulated lung cell suspensions of HDM-allergic mice. The diet containing FFBB reduced IL-6, IFN-γ, IL-4 and IL-10 concentrations, whereas the combination of galacto-oligosaccharides and long-chain fructo-oligosaccharides with BB was less potent in this model. CONCLUSION: These findings show that synbiotic dietary supplementation can affect respiratory allergic inflammation induced by HDM. The combination of FFBB was most effective in the prevention of HDM-induced airway inflammation in mice.