15 1 General Introduction In Chapter 2, macrophages’ role in the development of obesity and diabetes mellitus type II was reviewed. Insight into the different subsets associated with these diseases and how their metabolism changes depending on their microenvironment was provided. This chapter also describes different available possibilities for measuring cellular metabolites. In Chapter 3, we investigated whether the shown anti-inflammatory effects of KDACis in the COPD context apply also in our cell model of primary murine alveolar-like macrophages after lipopolysaccharide (LPS)-induced activation. We hypothesized that these anti-inflammatory effects may be associated with metabolic changes in macrophages. To validate this hypothesis, an unbiased and a targeted proteomic approach to investigate metabolic enzymes as well as LC- and GC-MS to quantify metabolites in combination with the measurement of functional parameters was used. While minimal metabolic changes were observed, KDAC inhibition reduced the production of inflammatory mediators. Interestingly, it specifically enhanced the expression of proteins involved in ubiquitination. The findings highlight the potential of KDAC inhibitors as anti-inflammatory drugs for diseases like COPD. In Chapter 4, primary murine alveolar-like macrophages to examine the impact of collagen morphology on macrophage marker expression, behaviour, and shape were used. Proteomic analysis revealed increased expression of glycolysis-related proteins, although this did not result in higher glycolytic activity, potentially due to reduced enzyme activity. Overall, our findings indicate that macrophages can detect collagen morphologies and adjust the expression and activity of metabolismrelated proteins. This suggests a significant interplay between macrophages and their microenvironment, which could be crucial in the progression of tissue repair to fibrosis in the lungs. Finally, in Chapter 5, the conclusions of this thesis are summarized and future implications are examined. The research presented in this thesis establishes a foundation for gaining a deeper understanding of macrophages and their intricate relationship with metabolism, as well as the implications of these metabolic changes in chronic diseases. These findings open up possibilities for therapeutic interventions targeting chronic inflammation.
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