11 1 General Introduction a relatively homogeneous population of cells. However, recent advances in singlecell sequencing have revealed the heterogeneity of AMs in healthy individuals. Studies have identified at least four superclusters of AMs with distinct subclusters, characterized by different gene expression profiles (36). One of the key factors contributing to the heterogeneity of AMs is the highly regulated production of specific combinations of chemokines, metallothioneins, interferon (IFN)-inducible genes, cholesterol-biosynthesis-related genes, and insulin-like growth factor 1 (IGF1) by different subsets of AMs. These subsets exhibit unique functional properties and may play specialized roles in immune responses and tissue homeostasis. Moreover, the observed heterogeneity of AMs is not limited to healthy individuals but extends to various lung diseases. Studies investigating diseases such as cystic fibrosis, COPD, and COVID-19 have consistently demonstrated the presence of these superclusters and subclusters across different individuals and disease conditions. This suggests that the heterogeneity of AMs is a universal feature and may have implications for understanding the pathogenesis and progression of lung diseases (37). In conclusion, lung macrophages, specifically alveolar macrophages, exhibit unique characteristics and heterogeneity in the lung microenvironment. They are highly abundant in the lung and display distinct gene expression profiles and functional properties. Understanding the heterogeneity of AMs has the potential to shed light on their diverse roles in lung health and disease. METABOLIC REPROGRAMMING OF MACROPHAGES Macrophages, as sentinel cells, need to respond rapidly to alterations in their microenvironment. They modify their metabolic pathways to ensure proper activation and function. One of the initial differences observed in macrophage metabolism during polarization is the alteration of amino acid metabolism. Classically activated macrophages convert arginine to nitric oxide (NO) and citrulline, while alternatively activated macrophages convert arginine to proline and polyamines (38). Furthermore, macrophages can reprogram their energy generation methods. Nonpolarized or alternatively activated macrophages use fatty acid beta-oxidation and mitochondrial oxidative phosphorylation (OXPHOS) to produce ATP (39). In contrast, pro-inflammatory stimuli induce a metabolic shift in macrophages towards aerobic glycolysis, similar to the Warburg effect observed in tumor cells (40). This metabolic reprogramming results in lactate secretion and the accumulation of citrate and succinate (41).
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