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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

Roles of citrate and succinate in macrophage and DC activation by LPS. Metabolic intermediates of the TCA cycle, such as citrate and succinate, can act as signaling molecules in macrophages and DCs, even when TCA cycle activity is decreased. LPS increases expression of the citrate carrier, Slc25a1, which could lead to increased transport of citrate out of the mitochondria. Citrate is then metabolized to acetyl-CoA and oxaloacetate by ACLY. Acetyl-CoA is used in fatty acid synthesis and also provides acetyl groups for acetylation of histone proteins. The conversion of oxaloacetate to pyruvate generates NADPH, which serves as a substrate in both iNOS-catalyzed NO production and NADPH oxidase-catalyzed ROS generation. NO nitrosylates and inhibits components of the mitochondrial electron transport chain and thus inhibits OXPHOS. ROS can stabilize HIF1α, and thus promote glycolysis and sustain transcription of the pro-inflammatory cytokine IL-1β. Succinate also promotes HIF-1α stabilization by inhibiting PHD enzymes, which, when active, hydroxylate and increase the degradation of HIF-1α. Succinate is also used to succinylate proteins, a post-translational modification with as yet unknown consequences. Sources of succinate in an LPS-activated macrophage include glutamine metabolism (anaplerosis and the GABA shunt), and possibly the glyoxylate shunt.
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fig3: Roles of citrate and succinate in macrophage and DC activation by LPS. Metabolic intermediates of the TCA cycle, such as citrate and succinate, can act as signaling molecules in macrophages and DCs, even when TCA cycle activity is decreased. LPS increases expression of the citrate carrier, Slc25a1, which could lead to increased transport of citrate out of the mitochondria. Citrate is then metabolized to acetyl-CoA and oxaloacetate by ACLY. Acetyl-CoA is used in fatty acid synthesis and also provides acetyl groups for acetylation of histone proteins. The conversion of oxaloacetate to pyruvate generates NADPH, which serves as a substrate in both iNOS-catalyzed NO production and NADPH oxidase-catalyzed ROS generation. NO nitrosylates and inhibits components of the mitochondrial electron transport chain and thus inhibits OXPHOS. ROS can stabilize HIF1α, and thus promote glycolysis and sustain transcription of the pro-inflammatory cytokine IL-1β. Succinate also promotes HIF-1α stabilization by inhibiting PHD enzymes, which, when active, hydroxylate and increase the degradation of HIF-1α. Succinate is also used to succinylate proteins, a post-translational modification with as yet unknown consequences. Sources of succinate in an LPS-activated macrophage include glutamine metabolism (anaplerosis and the GABA shunt), and possibly the glyoxylate shunt.

Mentions: These changes in citrate transport and metabolism (Figure 3) would therefore appear to be critical for the activation of macrophages and DCs by LPS, the latter in turn triggers T-cell activation and adaptive immunity.


Metabolic reprogramming in macrophages and dendritic cells in innate immunity.

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

Roles of citrate and succinate in macrophage and DC activation by LPS. Metabolic intermediates of the TCA cycle, such as citrate and succinate, can act as signaling molecules in macrophages and DCs, even when TCA cycle activity is decreased. LPS increases expression of the citrate carrier, Slc25a1, which could lead to increased transport of citrate out of the mitochondria. Citrate is then metabolized to acetyl-CoA and oxaloacetate by ACLY. Acetyl-CoA is used in fatty acid synthesis and also provides acetyl groups for acetylation of histone proteins. The conversion of oxaloacetate to pyruvate generates NADPH, which serves as a substrate in both iNOS-catalyzed NO production and NADPH oxidase-catalyzed ROS generation. NO nitrosylates and inhibits components of the mitochondrial electron transport chain and thus inhibits OXPHOS. ROS can stabilize HIF1α, and thus promote glycolysis and sustain transcription of the pro-inflammatory cytokine IL-1β. Succinate also promotes HIF-1α stabilization by inhibiting PHD enzymes, which, when active, hydroxylate and increase the degradation of HIF-1α. Succinate is also used to succinylate proteins, a post-translational modification with as yet unknown consequences. Sources of succinate in an LPS-activated macrophage include glutamine metabolism (anaplerosis and the GABA shunt), and possibly the glyoxylate shunt.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig3: Roles of citrate and succinate in macrophage and DC activation by LPS. Metabolic intermediates of the TCA cycle, such as citrate and succinate, can act as signaling molecules in macrophages and DCs, even when TCA cycle activity is decreased. LPS increases expression of the citrate carrier, Slc25a1, which could lead to increased transport of citrate out of the mitochondria. Citrate is then metabolized to acetyl-CoA and oxaloacetate by ACLY. Acetyl-CoA is used in fatty acid synthesis and also provides acetyl groups for acetylation of histone proteins. The conversion of oxaloacetate to pyruvate generates NADPH, which serves as a substrate in both iNOS-catalyzed NO production and NADPH oxidase-catalyzed ROS generation. NO nitrosylates and inhibits components of the mitochondrial electron transport chain and thus inhibits OXPHOS. ROS can stabilize HIF1α, and thus promote glycolysis and sustain transcription of the pro-inflammatory cytokine IL-1β. Succinate also promotes HIF-1α stabilization by inhibiting PHD enzymes, which, when active, hydroxylate and increase the degradation of HIF-1α. Succinate is also used to succinylate proteins, a post-translational modification with as yet unknown consequences. Sources of succinate in an LPS-activated macrophage include glutamine metabolism (anaplerosis and the GABA shunt), and possibly the glyoxylate shunt.
Mentions: These changes in citrate transport and metabolism (Figure 3) would therefore appear to be critical for the activation of macrophages and DCs by LPS, the latter in turn triggers T-cell activation and adaptive immunity.

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