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Time and Demand are Two Critical Dimensions of Immunometabolism: The Process of Macrophage Activation and the Pentose Phosphate Pathway.

Nagy C, Haschemi A - Front Immunol (2015)

Bottom Line: This perspective article starts by presenting an early attempt to investigate the physiology of inflammation, in order to illustrate one of the basic concepts of immunometabolism, wherein an adapted metabolism of infiltrating immune cells affects tissue function and inflammation.In the last section, we will provide information on how the pentose phosphate pathway may be of importance to provide both nucleotide precursors and redox-equivalents, and speculate how carbon-scrambling events in the non-oxidative pentose phosphate pathway might be regulated within cells by demand.We conclude that the adapted metabolism of inflammation is specific in respect to the effector-function and appears as a well-orchestrated event, dynamic by nature, and based on a functional interplay of signaling- and metabolic-pathways.

View Article: PubMed Central - PubMed

Affiliation: Department of Laboratory Medicine (KILM), Medical University of Vienna , Vienna , Austria.

ABSTRACT
A process is a function of time; in immunometabolism, this is reflected by the stepwise adaptation of metabolism to sustain the bio-energetic demand of an immune-response in its various states and shades. This perspective article starts by presenting an early attempt to investigate the physiology of inflammation, in order to illustrate one of the basic concepts of immunometabolism, wherein an adapted metabolism of infiltrating immune cells affects tissue function and inflammation. We then focus on the process of macrophage activation and aim to delineate the factor time within the current molecular context of metabolic-rewiring important for adapting primary carbohydrate metabolism. In the last section, we will provide information on how the pentose phosphate pathway may be of importance to provide both nucleotide precursors and redox-equivalents, and speculate how carbon-scrambling events in the non-oxidative pentose phosphate pathway might be regulated within cells by demand. We conclude that the adapted metabolism of inflammation is specific in respect to the effector-function and appears as a well-orchestrated event, dynamic by nature, and based on a functional interplay of signaling- and metabolic-pathways.

No MeSH data available.


Time-resolved metabolic reprograming during pro-inflammatory macrophage polarization. This model illustrates the activation of a macrophage as a function of time and is based on the literature discussed in the main text. LPS-induced activation can be grouped into an initiation-, an early metabolic-reprograming,- and an amplification-phase. The initiation phase of the metabolic response is characterized by an increase in glucose consumption and in the extracellular acidification rate (ECAR). The early metabolic reprograming phase depicts the increase and rerouting of carbon flux through glycolysis and the PPP, events which also regulate the cellular redox-state. In this setting, the mitochondrial association of hexokinase-II (HKII) appears to provide sufficient levels of glucose 6-phosphate (G6P), while the downregulation of sedoheptulose kinase (Shpk, previously known as CARKL) appears to be necessary to maintain appropriate carbon flux at the interface of glycolysis and the PPP. During the amplification phase, this pro-glycolytic metabolic-phenotype is further strengthened. A switch toward the more active 6-phosphofructo-2-kinase (PFK2) enzyme PFKFB3 produces higher levels of fructose 2-bisphosphate [F2,6bP], thus allosterically activating PFK1 and enhancing glycolytic flux. Dimers of the pyruvate kinase M2 (PKM2), as well as accumulating succinate further augment metabolic reprograming by supporting HIF-1α dependent transcriptional induction of glycolytic genes. In the amplification phase, also the export of intracellular glycolysis-derived lactate through monocarboxylate transporter 4 (MCT4) becomes obligatory, which may otherwise inhibit PFK1. These initial events lead to more prominent metabolic changes observed 24 h after macrophages have encountered the pro-inflammatory stimuli. However, further time-resolved data is required to refine these processes and our current perspective, how cellular metabolism of macrophages adapts during activation.
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Figure 1: Time-resolved metabolic reprograming during pro-inflammatory macrophage polarization. This model illustrates the activation of a macrophage as a function of time and is based on the literature discussed in the main text. LPS-induced activation can be grouped into an initiation-, an early metabolic-reprograming,- and an amplification-phase. The initiation phase of the metabolic response is characterized by an increase in glucose consumption and in the extracellular acidification rate (ECAR). The early metabolic reprograming phase depicts the increase and rerouting of carbon flux through glycolysis and the PPP, events which also regulate the cellular redox-state. In this setting, the mitochondrial association of hexokinase-II (HKII) appears to provide sufficient levels of glucose 6-phosphate (G6P), while the downregulation of sedoheptulose kinase (Shpk, previously known as CARKL) appears to be necessary to maintain appropriate carbon flux at the interface of glycolysis and the PPP. During the amplification phase, this pro-glycolytic metabolic-phenotype is further strengthened. A switch toward the more active 6-phosphofructo-2-kinase (PFK2) enzyme PFKFB3 produces higher levels of fructose 2-bisphosphate [F2,6bP], thus allosterically activating PFK1 and enhancing glycolytic flux. Dimers of the pyruvate kinase M2 (PKM2), as well as accumulating succinate further augment metabolic reprograming by supporting HIF-1α dependent transcriptional induction of glycolytic genes. In the amplification phase, also the export of intracellular glycolysis-derived lactate through monocarboxylate transporter 4 (MCT4) becomes obligatory, which may otherwise inhibit PFK1. These initial events lead to more prominent metabolic changes observed 24 h after macrophages have encountered the pro-inflammatory stimuli. However, further time-resolved data is required to refine these processes and our current perspective, how cellular metabolism of macrophages adapts during activation.

Mentions: Macrophages are important immune cells, which regulate tissue homeostasis by sensing and interpreting cell injury and infection, the classic triggers of an inflammatory response (12). Today, macrophages are classified according to the activation stimuli into at least two polarization states, the classic M1 (representing a pro-inflammatory phenotype) and the alternative M2 macrophage (representing an anti-inflammatory or homeostasis inducing phenotype), in order to discriminate between the effector phenotypes resulting from the distinct activation signals (13). However, in vivo macrophages rather appear to blend into various “shades of activation,” while retaining some of their plasticity (14–18). Furthermore, macrophage populations and phenotypes can dramatically change over time, as exemplified by the finding that the inflammatory response is a spatially and temporally coordinated process. Recently, the polarization process of macrophages has been further associated with the reprograming of cellular metabolism (19–25). Information processing by signal-transduction pathways starts shortly after activation and is temporally coordinated, reflected by the phosphorylation and de-phosphorylation of signal transducers and effector molecules. The question arises how the reprograming of primary carbohydrate metabolism is timed in the process of macrophage activation. We would like to present more detailed and more importantly time-resolved information on key events, which appear to establish a pro-inflammatory M1-like metabolic-phenotype induced by lipopolysaccharide (LPS, Figure 1).


Time and Demand are Two Critical Dimensions of Immunometabolism: The Process of Macrophage Activation and the Pentose Phosphate Pathway.

Nagy C, Haschemi A - Front Immunol (2015)

Time-resolved metabolic reprograming during pro-inflammatory macrophage polarization. This model illustrates the activation of a macrophage as a function of time and is based on the literature discussed in the main text. LPS-induced activation can be grouped into an initiation-, an early metabolic-reprograming,- and an amplification-phase. The initiation phase of the metabolic response is characterized by an increase in glucose consumption and in the extracellular acidification rate (ECAR). The early metabolic reprograming phase depicts the increase and rerouting of carbon flux through glycolysis and the PPP, events which also regulate the cellular redox-state. In this setting, the mitochondrial association of hexokinase-II (HKII) appears to provide sufficient levels of glucose 6-phosphate (G6P), while the downregulation of sedoheptulose kinase (Shpk, previously known as CARKL) appears to be necessary to maintain appropriate carbon flux at the interface of glycolysis and the PPP. During the amplification phase, this pro-glycolytic metabolic-phenotype is further strengthened. A switch toward the more active 6-phosphofructo-2-kinase (PFK2) enzyme PFKFB3 produces higher levels of fructose 2-bisphosphate [F2,6bP], thus allosterically activating PFK1 and enhancing glycolytic flux. Dimers of the pyruvate kinase M2 (PKM2), as well as accumulating succinate further augment metabolic reprograming by supporting HIF-1α dependent transcriptional induction of glycolytic genes. In the amplification phase, also the export of intracellular glycolysis-derived lactate through monocarboxylate transporter 4 (MCT4) becomes obligatory, which may otherwise inhibit PFK1. These initial events lead to more prominent metabolic changes observed 24 h after macrophages have encountered the pro-inflammatory stimuli. However, further time-resolved data is required to refine these processes and our current perspective, how cellular metabolism of macrophages adapts during activation.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4389563&req=5

Figure 1: Time-resolved metabolic reprograming during pro-inflammatory macrophage polarization. This model illustrates the activation of a macrophage as a function of time and is based on the literature discussed in the main text. LPS-induced activation can be grouped into an initiation-, an early metabolic-reprograming,- and an amplification-phase. The initiation phase of the metabolic response is characterized by an increase in glucose consumption and in the extracellular acidification rate (ECAR). The early metabolic reprograming phase depicts the increase and rerouting of carbon flux through glycolysis and the PPP, events which also regulate the cellular redox-state. In this setting, the mitochondrial association of hexokinase-II (HKII) appears to provide sufficient levels of glucose 6-phosphate (G6P), while the downregulation of sedoheptulose kinase (Shpk, previously known as CARKL) appears to be necessary to maintain appropriate carbon flux at the interface of glycolysis and the PPP. During the amplification phase, this pro-glycolytic metabolic-phenotype is further strengthened. A switch toward the more active 6-phosphofructo-2-kinase (PFK2) enzyme PFKFB3 produces higher levels of fructose 2-bisphosphate [F2,6bP], thus allosterically activating PFK1 and enhancing glycolytic flux. Dimers of the pyruvate kinase M2 (PKM2), as well as accumulating succinate further augment metabolic reprograming by supporting HIF-1α dependent transcriptional induction of glycolytic genes. In the amplification phase, also the export of intracellular glycolysis-derived lactate through monocarboxylate transporter 4 (MCT4) becomes obligatory, which may otherwise inhibit PFK1. These initial events lead to more prominent metabolic changes observed 24 h after macrophages have encountered the pro-inflammatory stimuli. However, further time-resolved data is required to refine these processes and our current perspective, how cellular metabolism of macrophages adapts during activation.
Mentions: Macrophages are important immune cells, which regulate tissue homeostasis by sensing and interpreting cell injury and infection, the classic triggers of an inflammatory response (12). Today, macrophages are classified according to the activation stimuli into at least two polarization states, the classic M1 (representing a pro-inflammatory phenotype) and the alternative M2 macrophage (representing an anti-inflammatory or homeostasis inducing phenotype), in order to discriminate between the effector phenotypes resulting from the distinct activation signals (13). However, in vivo macrophages rather appear to blend into various “shades of activation,” while retaining some of their plasticity (14–18). Furthermore, macrophage populations and phenotypes can dramatically change over time, as exemplified by the finding that the inflammatory response is a spatially and temporally coordinated process. Recently, the polarization process of macrophages has been further associated with the reprograming of cellular metabolism (19–25). Information processing by signal-transduction pathways starts shortly after activation and is temporally coordinated, reflected by the phosphorylation and de-phosphorylation of signal transducers and effector molecules. The question arises how the reprograming of primary carbohydrate metabolism is timed in the process of macrophage activation. We would like to present more detailed and more importantly time-resolved information on key events, which appear to establish a pro-inflammatory M1-like metabolic-phenotype induced by lipopolysaccharide (LPS, Figure 1).

Bottom Line: This perspective article starts by presenting an early attempt to investigate the physiology of inflammation, in order to illustrate one of the basic concepts of immunometabolism, wherein an adapted metabolism of infiltrating immune cells affects tissue function and inflammation.In the last section, we will provide information on how the pentose phosphate pathway may be of importance to provide both nucleotide precursors and redox-equivalents, and speculate how carbon-scrambling events in the non-oxidative pentose phosphate pathway might be regulated within cells by demand.We conclude that the adapted metabolism of inflammation is specific in respect to the effector-function and appears as a well-orchestrated event, dynamic by nature, and based on a functional interplay of signaling- and metabolic-pathways.

View Article: PubMed Central - PubMed

Affiliation: Department of Laboratory Medicine (KILM), Medical University of Vienna , Vienna , Austria.

ABSTRACT
A process is a function of time; in immunometabolism, this is reflected by the stepwise adaptation of metabolism to sustain the bio-energetic demand of an immune-response in its various states and shades. This perspective article starts by presenting an early attempt to investigate the physiology of inflammation, in order to illustrate one of the basic concepts of immunometabolism, wherein an adapted metabolism of infiltrating immune cells affects tissue function and inflammation. We then focus on the process of macrophage activation and aim to delineate the factor time within the current molecular context of metabolic-rewiring important for adapting primary carbohydrate metabolism. In the last section, we will provide information on how the pentose phosphate pathway may be of importance to provide both nucleotide precursors and redox-equivalents, and speculate how carbon-scrambling events in the non-oxidative pentose phosphate pathway might be regulated within cells by demand. We conclude that the adapted metabolism of inflammation is specific in respect to the effector-function and appears as a well-orchestrated event, dynamic by nature, and based on a functional interplay of signaling- and metabolic-pathways.

No MeSH data available.