(639c) Dissecting Metabolic Landscape of Alveolar Macrophages

Alveolar macrophages (AM) play a crucial role in the immune defense of the lung by undergoing polarization leading to proinflammatory or classically activated (M1) and anti-inflammatory or alternatively activated (M2) macrophages. The complex regulatory mechanism of M1 and M2 polarization is a fundamental step to fight against pathogens, yet the mechanism is not copiously understood. Genome-scale metabolic models (GEMs) have emerged as a powerful tool to study complex biological systems and shed light on the underlying mechanisms. In this study, we generated GEMs of healthy AM, M1 phase AM, and M2 phase AM from global human metabolic reconstruction, Human1. The in-silico models are capable of reproducing key metabolic phenomena such as experimentally verified Nitric Oxide (NO) and ATP production rates in healthy AMs, enhanced metabolic activities of Glycolysis and, Pentose Phosphate Pathway in the M1 phase, and upregulated Oxidative Phosphorylation, uninterrupted Tricarboxylic Acid Cycle (TCA) in M2 phase. The calculation of Gibbs free energy at different temperatures indicated increased metabolic rates with elevated temperature providing insight into the preliminary stages of pathogenesis. Exhaustive dissection of the positive/negative contribution of each pathway revealed the importance of NO production, the mechanisms of carnitine shuttle (mitochondria), Bile Acid Synthesis, and Pyruvate Metabolism in the immune response of the AM, and the distinct roles of M1 and M2 phases are further clarified. Future exploration of the generated models can lead to the study of dynamic interactions between the immune system and respiratory pathogens to develop novel therapeutic stratagems.