Limits...
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

Mechanisms of LPS-induced Warburg metabolism in macrophages or DCs. Upon LPS stimulation of TLR4, a range of metabolic changes occur in macrophages or DCs. (1) LPS activation upregulates iNOS expression, increasing the production of NO, which nitrosylates and thus inhibits target proteins in the mitochondrial electron transport chain, thereby dampening OXPHOS. (2) LPS activates mTOR, thereby increasing the translation of mRNA with 5′-TOP sequences, including HIF-1α mRNA. HIF-1α then increases expression of its target genes. (3) LPS increases expression of u-PFK2, an isoform of PFK2, thereby increasing levels of the metabolite F-2,6-BP. F-2,6-BP activates the glycolytic enzyme 6-phosphofructo-1-kinase. (4) Finally, LPS inhibits AMPK, resulting in decreased β-oxidation of fatty acids and mitochondrial biogenesis.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4493277&req=5

fig2: Mechanisms of LPS-induced Warburg metabolism in macrophages or DCs. Upon LPS stimulation of TLR4, a range of metabolic changes occur in macrophages or DCs. (1) LPS activation upregulates iNOS expression, increasing the production of NO, which nitrosylates and thus inhibits target proteins in the mitochondrial electron transport chain, thereby dampening OXPHOS. (2) LPS activates mTOR, thereby increasing the translation of mRNA with 5′-TOP sequences, including HIF-1α mRNA. HIF-1α then increases expression of its target genes. (3) LPS increases expression of u-PFK2, an isoform of PFK2, thereby increasing levels of the metabolite F-2,6-BP. F-2,6-BP activates the glycolytic enzyme 6-phosphofructo-1-kinase. (4) Finally, LPS inhibits AMPK, resulting in decreased β-oxidation of fatty acids and mitochondrial biogenesis.

Mentions: Substantial insights have been made into the underlying mechanisms of this metabolic switch. There are at least four main processes leading to Warburg metabolism in LPS-activated macrophages and DCs (Figure 2). As the majority of studies investigating this mechanism use LPS as a stimulus, this review focuses on the metabolic alterations induced by LPS in macrophages and DCs. Other innate immune cell stimuli also alter metabolic parameters in innate immune cells, including IFNγ11, poly(I:C)11, and infection with bacterial species such as Listeria monocytogenes, Mycobacterium bovis BCG19, and Salmonella typhimurium17.


Metabolic reprogramming in macrophages and dendritic cells in innate immunity.

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

Mechanisms of LPS-induced Warburg metabolism in macrophages or DCs. Upon LPS stimulation of TLR4, a range of metabolic changes occur in macrophages or DCs. (1) LPS activation upregulates iNOS expression, increasing the production of NO, which nitrosylates and thus inhibits target proteins in the mitochondrial electron transport chain, thereby dampening OXPHOS. (2) LPS activates mTOR, thereby increasing the translation of mRNA with 5′-TOP sequences, including HIF-1α mRNA. HIF-1α then increases expression of its target genes. (3) LPS increases expression of u-PFK2, an isoform of PFK2, thereby increasing levels of the metabolite F-2,6-BP. F-2,6-BP activates the glycolytic enzyme 6-phosphofructo-1-kinase. (4) Finally, LPS inhibits AMPK, resulting in decreased β-oxidation of fatty acids and mitochondrial biogenesis.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig2: Mechanisms of LPS-induced Warburg metabolism in macrophages or DCs. Upon LPS stimulation of TLR4, a range of metabolic changes occur in macrophages or DCs. (1) LPS activation upregulates iNOS expression, increasing the production of NO, which nitrosylates and thus inhibits target proteins in the mitochondrial electron transport chain, thereby dampening OXPHOS. (2) LPS activates mTOR, thereby increasing the translation of mRNA with 5′-TOP sequences, including HIF-1α mRNA. HIF-1α then increases expression of its target genes. (3) LPS increases expression of u-PFK2, an isoform of PFK2, thereby increasing levels of the metabolite F-2,6-BP. F-2,6-BP activates the glycolytic enzyme 6-phosphofructo-1-kinase. (4) Finally, LPS inhibits AMPK, resulting in decreased β-oxidation of fatty acids and mitochondrial biogenesis.
Mentions: Substantial insights have been made into the underlying mechanisms of this metabolic switch. There are at least four main processes leading to Warburg metabolism in LPS-activated macrophages and DCs (Figure 2). As the majority of studies investigating this mechanism use LPS as a stimulus, this review focuses on the metabolic alterations induced by LPS in macrophages and DCs. Other innate immune cell stimuli also alter metabolic parameters in innate immune cells, including IFNγ11, poly(I:C)11, and infection with bacterial species such as Listeria monocytogenes, Mycobacterium bovis BCG19, and Salmonella typhimurium17.

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