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Metabolic reprogramming in macrophages and dendritic cells in innate immunity.

Kelly B, O'Neill LA - Cell Res. (2015)

Bottom Line: Interference with this process actually abolishes the ability of DCs to activate T cells.Another TCA cycle intermediate, succinate, activates HIF-1α and promotes inflammatory gene expression.These new insights are providing us with a deeper understanding of the role of metabolic reprogramming in innate immunity.

View Article: PubMed Central - PubMed

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

ABSTRACT
Activation of macrophages and dendritic cells (DCs) by pro-inflammatory stimuli causes them to undergo a metabolic switch towards glycolysis and away from oxidative phosphorylation (OXPHOS), similar to the Warburg effect in tumors. However, it is only recently that the mechanisms responsible for this metabolic reprogramming have been elucidated in more detail. The transcription factor hypoxia-inducible factor-1α (HIF-1α) plays an important role under conditions of both hypoxia and normoxia. The withdrawal of citrate from the tricarboxylic acid (TCA) cycle has been shown to be critical for lipid biosynthesis in both macrophages and DCs. Interference with this process actually abolishes the ability of DCs to activate T cells. Another TCA cycle intermediate, succinate, activates HIF-1α and promotes inflammatory gene expression. These new insights are providing us with a deeper understanding of the role of metabolic reprogramming in innate immunity.

No MeSH data available.


Related in: MedlinePlus

The Warburg effect. (A) In resting cells, glucose is metabolized to pyruvate via glycolysis. Some pyruvate is converted to lactate, but most is directed to the TCA cycle via acetyl-CoA. The TCA cycle generates NADH, which donates electrons to the mitochondrial electron transport chain so that OXPHOS can progress. (B) In highly proliferative or tumour cells, the metabolic profile switches from OXPHOS to aerobic glycolysis, known as the Warburg effect. Mature innate immune cells also rely on glycolysis, although they do not proliferate after activation. The majority of the pyruvate generated by glycolysis is converted to lactate, and glycolytic intermediates build up, meeting the high energy demand of the cell. Glycolysis is the source of ATP in these cells, and also provides glucose-6-phosphate for nucleotide biosynthesis in the PPP.
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fig1: The Warburg effect. (A) In resting cells, glucose is metabolized to pyruvate via glycolysis. Some pyruvate is converted to lactate, but most is directed to the TCA cycle via acetyl-CoA. The TCA cycle generates NADH, which donates electrons to the mitochondrial electron transport chain so that OXPHOS can progress. (B) In highly proliferative or tumour cells, the metabolic profile switches from OXPHOS to aerobic glycolysis, known as the Warburg effect. Mature innate immune cells also rely on glycolysis, although they do not proliferate after activation. The majority of the pyruvate generated by glycolysis is converted to lactate, and glycolytic intermediates build up, meeting the high energy demand of the cell. Glycolysis is the source of ATP in these cells, and also provides glucose-6-phosphate for nucleotide biosynthesis in the PPP.

Mentions: The Warburg effect is an important concept for understanding metabolic changes occurring in innate immune cells upon activation3. Otto Warburg described a metabolic profile of tumors in normoxic conditions, in which glycolysis predominates even though there is oxygen available for oxidative metabolism to proceed. Pyruvate that is produced by the glycolytic pathway, instead of feeding into the tricarboxylic acid (TCA) cycle and subsequent oxidative phosphorylation (OXPHOS), is metabolized to lactate. The Warburg Effect is depicted in Figure 1.


Metabolic reprogramming in macrophages and dendritic cells in innate immunity.

Kelly B, O'Neill LA - Cell Res. (2015)

The Warburg effect. (A) In resting cells, glucose is metabolized to pyruvate via glycolysis. Some pyruvate is converted to lactate, but most is directed to the TCA cycle via acetyl-CoA. The TCA cycle generates NADH, which donates electrons to the mitochondrial electron transport chain so that OXPHOS can progress. (B) In highly proliferative or tumour cells, the metabolic profile switches from OXPHOS to aerobic glycolysis, known as the Warburg effect. Mature innate immune cells also rely on glycolysis, although they do not proliferate after activation. The majority of the pyruvate generated by glycolysis is converted to lactate, and glycolytic intermediates build up, meeting the high energy demand of the cell. Glycolysis is the source of ATP in these cells, and also provides glucose-6-phosphate for nucleotide biosynthesis in the PPP.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4493277&req=5

fig1: The Warburg effect. (A) In resting cells, glucose is metabolized to pyruvate via glycolysis. Some pyruvate is converted to lactate, but most is directed to the TCA cycle via acetyl-CoA. The TCA cycle generates NADH, which donates electrons to the mitochondrial electron transport chain so that OXPHOS can progress. (B) In highly proliferative or tumour cells, the metabolic profile switches from OXPHOS to aerobic glycolysis, known as the Warburg effect. Mature innate immune cells also rely on glycolysis, although they do not proliferate after activation. The majority of the pyruvate generated by glycolysis is converted to lactate, and glycolytic intermediates build up, meeting the high energy demand of the cell. Glycolysis is the source of ATP in these cells, and also provides glucose-6-phosphate for nucleotide biosynthesis in the PPP.
Mentions: The Warburg effect is an important concept for understanding metabolic changes occurring in innate immune cells upon activation3. Otto Warburg described a metabolic profile of tumors in normoxic conditions, in which glycolysis predominates even though there is oxygen available for oxidative metabolism to proceed. Pyruvate that is produced by the glycolytic pathway, instead of feeding into the tricarboxylic acid (TCA) cycle and subsequent oxidative phosphorylation (OXPHOS), is metabolized to lactate. The Warburg Effect is depicted in Figure 1.

Bottom Line: Interference with this process actually abolishes the ability of DCs to activate T cells.Another TCA cycle intermediate, succinate, activates HIF-1α and promotes inflammatory gene expression.These new insights are providing us with a deeper understanding of the role of metabolic reprogramming in innate immunity.

View Article: PubMed Central - PubMed

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

ABSTRACT
Activation of macrophages and dendritic cells (DCs) by pro-inflammatory stimuli causes them to undergo a metabolic switch towards glycolysis and away from oxidative phosphorylation (OXPHOS), similar to the Warburg effect in tumors. However, it is only recently that the mechanisms responsible for this metabolic reprogramming have been elucidated in more detail. The transcription factor hypoxia-inducible factor-1α (HIF-1α) plays an important role under conditions of both hypoxia and normoxia. The withdrawal of citrate from the tricarboxylic acid (TCA) cycle has been shown to be critical for lipid biosynthesis in both macrophages and DCs. Interference with this process actually abolishes the ability of DCs to activate T cells. Another TCA cycle intermediate, succinate, activates HIF-1α and promotes inflammatory gene expression. These new insights are providing us with a deeper understanding of the role of metabolic reprogramming in innate immunity.

No MeSH data available.


Related in: MedlinePlus