(252c) Dissecting Metabolic Landscape of Alveolar Macrophage

Alveolar Macrophages (AM) play a pivotal role in safeguarding the lungs against inhaled particulates and pathogens, making them integral components of the respiratory defense system. Understanding the intricacies of AM metabolism is crucial for unraveling the mechanisms underlying immune responses in the lungs, thereby offering insights into the development of effective therapies for respiratory disorders. In this study, we delve into the metabolic dynamics of these highly plastic immune cells, which adopt either a classically activated M1 phenotype or an alternatively activated M2 phenotype in response to specific signals. Our investigation centers on reconstructing context-specific Genome-Scale Metabolic (GSM) models to elucidate the metabolic shifts occurring during AM activation phases (M1 and M2). We emphasize the catalytic role of temperature in shaping the immune response of these cells and pinpoint the involvement of key enzymes such as GRHPR (glyoxylate and hydroxypyruvate reductase), OCD1 (ornithine decarboxylase 1), GLS (glutaminase), and GNE (glucosamine (UDP-N-acetyl)-2-epimerase/N-acetylmannosamine kinase) in macrophage polarization. Through our analysis, we highlight the critical involvement of pathways including pyruvate metabolism, arachidonic acid metabolism, chondroitin/heparan sulfate biosynthesis, and heparan sulfate degradation in driving the transition between M1 and M2 phenotypes. Furthermore, we introduce a novel bilevel optimization framework called MetaShiftOptimizer, designed to identify minimal modifications capable of shifting AM from one activated state (M1/M2) to another. This framework allows us to pinpoint specific reactions and pathways crucial for the M1/M2 switch. Notably, reactions involved in glycogenin formation and transport, L-carnitine movement to mitochondria via the carnitine shuttle, as well as the generation of 5-hydroperoxyeicosatetraenoic acid and Leukotriene B4 through arachidonic acid metabolism, emerge as significant factors driving polarization shifts. These findings offer valuable insights for the development of efficient therapeutic targets aimed at addressing severe respiratory disorders in the future.