143 5 General Discussion Adipose tissue macrophages, which are often described as metabolically activated macrophages, are characterized by lipid uptake leading to foam cell formation in the setting of metabolic dysfunction (Chapter 2). Elevated lipids and glucose concentrations in the adipose tissue lead to changes in metabolism due to an increased energy demand accompanied by increased glycolytic activity, increased lactate production, increased oxidative phosphorylation, and activation of lysosomal pathways to catabolize the free fatty acids when compared to adipose tissue macrophages in lean individuals. Some of these metabolic changes are comparable to those in macrophages when activated by inflammatory stimuli such as LPS, including the use of glycolysis as the primary energy source, but the majority of these metabolic changes are specific to metabolically activated macrophages. In the lungs, there are three populations of macrophages: tissue-resident alveolar macrophages, monocyte-derived alveolar macrophages, and interstitial macrophages. Tissue-resident alveolar macrophages are the most abundant macrophages in the lungs residing in the airspaces of the lung alveoli. They play an essential role in defending the lung against foreign particles and pathogens and are involved in the regulation of lung inflammation. Monocyte-derived alveolar macrophages are derived from circulating monocytes and are recruited to the lungs in response to inflammation or injury. Interstitial macrophages are found in the lung connective tissue and are responsible for detecting and engulfing any foreign substances that enter the lung interstitium, and for interacting with the adaptive arm of the immune system [14]. In Chapters 3 and 4 tissue-resident alveolar-like macrophages were used as a model to show how macrophages shift their metabolism in response to stimuli or to different tissue environments. These cells, defined also as Max Plank Institute (MPI) cells, are self-renewing and non-transformed cells originating from fetal liver monocytes of C57BL/6J mice. MPI cells were used as a model of alveolar macrophages, as they functionally and phenotypically closely resemble tissueresident alveolar macrophages [15]. In Chapter 3 we investigated how murine alveolar-like macrophages change their metabolism after lipopolysaccharide (LPS)-induced activation in the presence or absence of two different lysine deacetylase inhibitors. We first studied whether these cells undergo classic metabolic reprogramming when treated with LPS as an inflammatory stimulus. Surprisingly, we found that these alveolar-like macrophages did not activate the glycolytic pathway, but rather undergo changes at the level of the TCA cycle, since the metabolites malate, succinate, and α-ketoglutarate were higher compared to control. This finding is in line with a break in the TCA cycle at two points, namely after succinate and citrate/isocitrate leading to the accumulation
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