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Metabolic reprograming in macrophage polarization.

Galván-Peña S, O'Neill LA - Front Immunol (2014)

Bottom Line: Studying the metabolism of immune cells in recent years has emphasized the tight link existing between the metabolic state and the phenotype of these cells.Alternatively activated or M2 macrophages on the other hand are involved in tissue repair and wound healing and use oxidative metabolism to fuel their longer-term functions.The potential to target these events and impact on disease is an exciting prospect.

View Article: PubMed Central - PubMed

Affiliation: School of Biochemistry and Immunology, Trinity Biomedical Science Institute, Trinity College Dublin , Dublin , Ireland.

ABSTRACT
Studying the metabolism of immune cells in recent years has emphasized the tight link existing between the metabolic state and the phenotype of these cells. Macrophages in particular are a good example of this phenomenon. Whether the macrophage obtains its energy through glycolysis or through oxidative metabolism can give rise to different phenotypes. Classically activated or M1 macrophages are key players of the first line of defense against bacterial infections and are known to obtain energy through glycolysis. Alternatively activated or M2 macrophages on the other hand are involved in tissue repair and wound healing and use oxidative metabolism to fuel their longer-term functions. Metabolic intermediates, however, are not just a source of energy but can be directly implicated in a particular macrophage phenotype. In M1 macrophages, the Krebs cycle intermediate succinate regulates HIF1α, which is responsible for driving the sustained production of the pro-inflammatory cytokine IL1β. In M2 macrophages, the sedoheptulose kinase carbohydrate kinase-like protein is critical for regulating the pentose phosphate pathway. The potential to target these events and impact on disease is an exciting prospect.

No MeSH data available.


Related in: MedlinePlus

Metabolic profile of an M1 macrophage is shown. Classically activated macrophages induce an aerobic glycolytic program that results in lactate production and increased levels of intermediates of the Krebs cycle. The HIF1α transcription factor also becomes activated and can drive production of pro-inflammatory cytokines. The key functional consequences are bacterial killing, mostly through the production of ROS and NO, and inflammation, which occurs via cytokine production. G6P, glucose-6-phosphate; F6P, fructose-6-phosphate; R5P, ribulose-5-phosphate; S7P, sedoheptulose phosphate; NO, nitric oxide; ROS, reactive-oxygen species.
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Figure 1: Metabolic profile of an M1 macrophage is shown. Classically activated macrophages induce an aerobic glycolytic program that results in lactate production and increased levels of intermediates of the Krebs cycle. The HIF1α transcription factor also becomes activated and can drive production of pro-inflammatory cytokines. The key functional consequences are bacterial killing, mostly through the production of ROS and NO, and inflammation, which occurs via cytokine production. G6P, glucose-6-phosphate; F6P, fructose-6-phosphate; R5P, ribulose-5-phosphate; S7P, sedoheptulose phosphate; NO, nitric oxide; ROS, reactive-oxygen species.

Mentions: In M1 macrophages, aerobic glycolysis is induced upon activation, which involves an increase in glucose uptake as well as the conversion of pyruvate to lactate (Figure 1). At the same time, the activities of the respiratory chain are attenuated, allowing for reactive-oxygen species (ROS) production. Further evidence for this is provided when treating macrophages with the electron transport chain inhibitors rotenone and antimycin A as this mimics the effects of toll-like receptor (TLR) agonists in driving ROS production from the mitochondria (10). Furthermore, the pentose phosphate pathway is also induced following classical activation. This pathway is key for the generation of NADPH for the NADPH oxidase, which is important for ROS production, but also for nitric oxide synthesis (11). Altogether, these metabolic events can provide the cell with rapid energy and reducing equivalents, which are required for bactericidal activity. M2 macrophages on the other hand obtain much of their energy from fatty acid oxidation and oxidative metabolism, which can be sustained for longer. Following activation, they can induce expression of constituents of the electron transport chain that will perform oxidative phosphorylation as well as driving the pyruvate into the Krebs cycle (Figure 2). The pentose phosphate pathway is also more limited in M2 macrophages. Blocking oxidative metabolism not only blocks the M2 phenotype but also drives the macrophage into an M1 state. Similarly, forcing oxidative metabolism in an M1 macrophage potentiates the M2 phenotype (12, 13). These key metabolic differences between differentially activated macrophages are widely accepted; however, the switches responsible for orchestrating these different profiles at the molecular level remain largely unknown and how exactly the cell’s metabolic status regulates polarization is not yet well understood.


Metabolic reprograming in macrophage polarization.

Galván-Peña S, O'Neill LA - Front Immunol (2014)

Metabolic profile of an M1 macrophage is shown. Classically activated macrophages induce an aerobic glycolytic program that results in lactate production and increased levels of intermediates of the Krebs cycle. The HIF1α transcription factor also becomes activated and can drive production of pro-inflammatory cytokines. The key functional consequences are bacterial killing, mostly through the production of ROS and NO, and inflammation, which occurs via cytokine production. G6P, glucose-6-phosphate; F6P, fructose-6-phosphate; R5P, ribulose-5-phosphate; S7P, sedoheptulose phosphate; NO, nitric oxide; ROS, reactive-oxygen species.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4151090&req=5

Figure 1: Metabolic profile of an M1 macrophage is shown. Classically activated macrophages induce an aerobic glycolytic program that results in lactate production and increased levels of intermediates of the Krebs cycle. The HIF1α transcription factor also becomes activated and can drive production of pro-inflammatory cytokines. The key functional consequences are bacterial killing, mostly through the production of ROS and NO, and inflammation, which occurs via cytokine production. G6P, glucose-6-phosphate; F6P, fructose-6-phosphate; R5P, ribulose-5-phosphate; S7P, sedoheptulose phosphate; NO, nitric oxide; ROS, reactive-oxygen species.
Mentions: In M1 macrophages, aerobic glycolysis is induced upon activation, which involves an increase in glucose uptake as well as the conversion of pyruvate to lactate (Figure 1). At the same time, the activities of the respiratory chain are attenuated, allowing for reactive-oxygen species (ROS) production. Further evidence for this is provided when treating macrophages with the electron transport chain inhibitors rotenone and antimycin A as this mimics the effects of toll-like receptor (TLR) agonists in driving ROS production from the mitochondria (10). Furthermore, the pentose phosphate pathway is also induced following classical activation. This pathway is key for the generation of NADPH for the NADPH oxidase, which is important for ROS production, but also for nitric oxide synthesis (11). Altogether, these metabolic events can provide the cell with rapid energy and reducing equivalents, which are required for bactericidal activity. M2 macrophages on the other hand obtain much of their energy from fatty acid oxidation and oxidative metabolism, which can be sustained for longer. Following activation, they can induce expression of constituents of the electron transport chain that will perform oxidative phosphorylation as well as driving the pyruvate into the Krebs cycle (Figure 2). The pentose phosphate pathway is also more limited in M2 macrophages. Blocking oxidative metabolism not only blocks the M2 phenotype but also drives the macrophage into an M1 state. Similarly, forcing oxidative metabolism in an M1 macrophage potentiates the M2 phenotype (12, 13). These key metabolic differences between differentially activated macrophages are widely accepted; however, the switches responsible for orchestrating these different profiles at the molecular level remain largely unknown and how exactly the cell’s metabolic status regulates polarization is not yet well understood.

Bottom Line: Studying the metabolism of immune cells in recent years has emphasized the tight link existing between the metabolic state and the phenotype of these cells.Alternatively activated or M2 macrophages on the other hand are involved in tissue repair and wound healing and use oxidative metabolism to fuel their longer-term functions.The potential to target these events and impact on disease is an exciting prospect.

View Article: PubMed Central - PubMed

Affiliation: School of Biochemistry and Immunology, Trinity Biomedical Science Institute, Trinity College Dublin , Dublin , Ireland.

ABSTRACT
Studying the metabolism of immune cells in recent years has emphasized the tight link existing between the metabolic state and the phenotype of these cells. Macrophages in particular are a good example of this phenomenon. Whether the macrophage obtains its energy through glycolysis or through oxidative metabolism can give rise to different phenotypes. Classically activated or M1 macrophages are key players of the first line of defense against bacterial infections and are known to obtain energy through glycolysis. Alternatively activated or M2 macrophages on the other hand are involved in tissue repair and wound healing and use oxidative metabolism to fuel their longer-term functions. Metabolic intermediates, however, are not just a source of energy but can be directly implicated in a particular macrophage phenotype. In M1 macrophages, the Krebs cycle intermediate succinate regulates HIF1α, which is responsible for driving the sustained production of the pro-inflammatory cytokine IL1β. In M2 macrophages, the sedoheptulose kinase carbohydrate kinase-like protein is critical for regulating the pentose phosphate pathway. The potential to target these events and impact on disease is an exciting prospect.

No MeSH data available.


Related in: MedlinePlus