Malla Sunayana, Sajeevan Karuna Anna, Acharya Bibek, Chowdhury Ratul, Saha Rajib
Chemical and Biomolecular Engineering, University of Nebraska-Lincoln, Lincoln, NE, USA.
Chemical and Biological Engineering, Iowa State University, Ames, IA, USA.
Sci Rep. 2024 Dec 5;14(1):30383. doi: 10.1038/s41598-024-81253-w.
The highly plastic nature of Alveolar Macrophage (AM) plays a crucial role in the defense against inhaled particulates and pathogens in the lungs. Depending on the signal, AM acquires either the classically activated M1 phenotype or the alternatively activated M2 phenotype. In this study, we investigate the metabolic shift in the activated phases of AM (M1 and M2 phases) by reconstructing context specific Genome-Scale Metabolic (GSM) models. Metabolic pathways such as pyruvate metabolism, arachidonic acid metabolism, chondroitin/heparan sulfate biosynthesis, and heparan sulfate degradation are found to be important driving forces in the development of the M1/M2 phenotypes. Additionally, we formulated a bilevel optimization framework named MetaShiftOptimizer to identify minimal modifications that shift one activated state (M1/M2) to the other. The identified reactions involve metabolites such as glycogenin, L-carnitine, 5-hydroperoxy eicosatetraenoic acid, and leukotriene B4, which show potential to be further investigated as significant factors for developing efficient therapy targets for severe respiratory disorders in the future. Overall, our study contributes to the understanding of the metabolic capabilities of the M1 and M2 phenotype of AM and identifies pathways and reactions that can be potential targets for polarization shift and also be used as therapeutic strategies against respiratory diseases.
肺泡巨噬细胞（AM）的高度可塑性在肺部抵御吸入颗粒物和病原体的过程中起着关键作用。根据信号的不同，AM可获得经典激活的M1表型或替代激活的M2表型。在本研究中，我们通过构建上下文特定的基因组规模代谢（GSM）模型，研究了AM激活阶段（M1和M2阶段）的代谢转变。发现丙酮酸代谢、花生四烯酸代谢、硫酸软骨素/硫酸乙酰肝素生物合成以及硫酸乙酰肝素降解等代谢途径是M1/M2表型发展的重要驱动力。此外，我们制定了一个名为MetaShiftOptimizer的双层优化框架，以确定将一种激活状态（M1/M2）转变为另一种激活状态所需的最小修饰。所确定的反应涉及糖原素、L-肉碱、5-氢过氧二十碳四烯酸和白三烯B4等代谢物，这些代谢物显示出在未来作为开发严重呼吸系统疾病有效治疗靶点的重要因素而有待进一步研究的潜力。总体而言，我们的研究有助于理解AM的M1和M2表型的代谢能力，并确定了可作为极化转变潜在靶点以及用于对抗呼吸系统疾病治疗策略的途径和反应。
