142 Chapter 5 Figure 1: Heatmap of normalized expression of transcripts per million per macrophage of metabolic genes in different tissues. On the x-axis are reported the genes belonging to the different metabolic pathways, which are highlighted on the top part of the figure, on the y-axis the different organs that were investigated are reported. A list of the analyzed genes is available in Supplementary Table 1. Altogether, our data highlight the necessity to investigate immunometabolism in a tissue-specific framework and emphasize that the mechanisms and consequences of innate memory are influenced by the local microenvironment and disease setting. MACROPHAGES SHIFT THEIR METABOLISM DEPENDING ON STIMULI AND TISSUE ENVIRONMENT. The work performed in this thesis has aided in gaining a better understanding of macrophage metabolism in different contexts. The literature review in Chapter 2 describes the classical view on macrophage metabolic reprogramming, based on the classification of M1 pro-inflammatory macrophages and M2 anti-inflammatory macrophages. M1 macrophages mainly rely on glycolysis as an energy source and a TCA cycle that is broken at two points, whereas M2 macrophages rely on fatty acid beta-oxidation and mitochondrial oxidative phosphorylation for energy. The overview in Chapter 2 and the work reported in this thesis show that this is an oversimplification. For example, adipose tissue macrophages polarize to a metabolically activated phenotype in the context of Diabetes Mellitus type 2 without obvious proinflammatory stimuli (Chapter 2), while alveolar-like macrophages respond to proinflammatory stimuli without relying on glycolysis as an energy source but mainly using mitochondrial respiration (Chapter 3), changing their metabolic sources based on the tissue environment, namely different types of collagen (Chapter 4).
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