Metabolic Regulation of Macrophage Activation

Abstract

Macrophages, the central mediators of innate immune responses, being in the first-line of defense, they have to readily respond to pathogenic or tissue damage signals to initiate the inflammatory cascade. Such rapid responses require energy to support orchestrated production of pro-inflammatory mediators and activation of phagocytosis. Being a cell type that is present in diverse environments and conditions, macrophages have to adapt to different nutritional resources. Thus, macrophages have developed plasticity and are capable of utilizing energy at both normoxic and hypoxic conditions and in the presence of varying concentrations of glucose or other nutrients. Such adaptation is reflected on changes in signaling pathways that modulate responses, accounting for the different activation phenotypes observed. Macrophage metabolism has been tightly associated with distinct activation phenotypes within the range of M1-like and M2-like types. In the context of diseases, systemic changes also affect macrophage metabolism, as in diabetes and insulin resistance, which results in altered metabolism and distinct activation phenotypes in the adipose tissue or in the periphery. In the context of solid tumors, tumor-associated macrophages adapt in the hypoxic environment, which results in metabolic changes that are reflected on an activation phenotype that supports tumor growth. Coordination of environmental and pathogenic signals determines macrophage metabolism, which in turn shapes the type and magnitude of the response. Therefore, modulating macrophage metabolism provides a potential therapeutic approach for inflammatory diseases and cancer.

Quantitative Proteomic Analysis of Mouse Sciatic Nerve Reveals Post-injury Upregulation of ADP-Dependent Glucokinase Promoting Macrophage Phagocytosis

“…Macrophages are the effector cells of the innate immune system and the professional phagocytes highly specialized in removal of cellular debris and dead/dying cells ( Kolliniati et al, 2021 ; Nazareth et al, 2021 ). To understand the functional relevance of ADPGK in macrophages in response to injury, we performed a macrophage phagocytosis assay using the engulfment of the IgG-coated beads as a readout (see section “Materials and Methods”).…”

Diabetes-Induced Changes in Macrophage Biology Might Lead to Reduced Risk for Abdominal Aortic Aneurysm Development

“…Additional experiments are required, such as lactate measurements and/or Seahorse experiments, to investigate the metabolic pathways involved in the observed increase in extracellular acidification. According to their inflammatory status, macrophages are classified as classical activated (pro-inflammatory, M1) and alternatively activated (anti-inflammatory, M2), a classification also associated with distinct metabolic activities [18]. Generally, pro-inflammatory M1 macrophages rely mainly on glycolysis, whereas anti-inflammatory M2 macrophages are more dependent on FAO.…”

Immunometabolism: Where Immunology and Metabolism Meet

“…Nati et al discuss the role of neutrophils and macrophages in the liver in the context of non-alcoholic fatty liver disease [18]. The other two review articles by Kolliniati et al and Ferreira et al focus, respectively, on the regulation of macrophage biology and the process of innate immune memory, by metabolic processes, such as glycolysis, the tricarboxylic acid cycle, lipid metabolism, or oxidative phosphorylation [19, 20]. Kolliniati et al review the impact of metabolic adaptations on macrophage plasticity and function in the context of different diseases, including cancer [20].…”

“…The other two review articles by Kolliniati et al and Ferreira et al focus, respectively, on the regulation of macrophage biology and the process of innate immune memory, by metabolic processes, such as glycolysis, the tricarboxylic acid cycle, lipid metabolism, or oxidative phosphorylation [19, 20]. Kolliniati et al review the impact of metabolic adaptations on macrophage plasticity and function in the context of different diseases, including cancer [20]. The article by Ferreira et al provides insights on the important contribution of metabolic and epigenetic rewiring of innate immune cells in the context of trained immunity [19].…”