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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

Metabolic differences between M1 and M2 macrophages. M1 macrophages rely on glycolysis for ATP production and have increased levels of iNOS, HIF-1α and u-PFK2, while M2 macrophages are fueled by OXPHOS and have increased levels of Arg-1, AMPK and PFKFB1. M1 macrophages release pro-inflammatory cytokines such as IL-1β, while M2 macrophages are involved in the response to parasite infection, as well as in wound healing, and they release the anti-inflammatory cytokine IL-10. In fact, it is thought that a spectrum of macrophage activation exists, with different populations of macrophages exhibiting different inflammatory and metabolic phenotypes.
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fig4: Metabolic differences between M1 and M2 macrophages. M1 macrophages rely on glycolysis for ATP production and have increased levels of iNOS, HIF-1α and u-PFK2, while M2 macrophages are fueled by OXPHOS and have increased levels of Arg-1, AMPK and PFKFB1. M1 macrophages release pro-inflammatory cytokines such as IL-1β, while M2 macrophages are involved in the response to parasite infection, as well as in wound healing, and they release the anti-inflammatory cytokine IL-10. In fact, it is thought that a spectrum of macrophage activation exists, with different populations of macrophages exhibiting different inflammatory and metabolic phenotypes.

Mentions: Many of the processes that drive the glycolytic switch in M1 macrophages are downregulated in M2 macrophages (Figure 4). First, arginase 1 (Arg-1) is highly expressed in M2 macrophages, while iNOS expression is decreased93. M1 macrophages have increased levels of citrulline and the inflammatory mediator NO, while in M2 macrophages, arginine is preferentially metabolized to urea and ornithine94. Ornithine can be further metabolized to polyamines and proline. Schistosome eggs induce Arg-1 expression in infected mice, and the combination of IL-4 and IL-13 increases proline production by macrophages93. This increased proline production could contribute to granuloma formation and liver fibrosis in infected mice, as both of these are enhanced when proline synthesis is boosted93. However, there is also conflicting evidence suggesting that Arg-1-expressing macrophages suppress schistosome-induced fibrosis during chronic infection95. Interestingly, Arg-1 can be induced in classically activated macrophages by intracellular infection with mycobacteria, and functions in this context to suppress NO production96. M. tuberculosis-infected mice lacking Arg-1 expression in macrophages are better able to clear the bacteria96.


Metabolic reprogramming in macrophages and dendritic cells in innate immunity.

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

Metabolic differences between M1 and M2 macrophages. M1 macrophages rely on glycolysis for ATP production and have increased levels of iNOS, HIF-1α and u-PFK2, while M2 macrophages are fueled by OXPHOS and have increased levels of Arg-1, AMPK and PFKFB1. M1 macrophages release pro-inflammatory cytokines such as IL-1β, while M2 macrophages are involved in the response to parasite infection, as well as in wound healing, and they release the anti-inflammatory cytokine IL-10. In fact, it is thought that a spectrum of macrophage activation exists, with different populations of macrophages exhibiting different inflammatory and metabolic phenotypes.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig4: Metabolic differences between M1 and M2 macrophages. M1 macrophages rely on glycolysis for ATP production and have increased levels of iNOS, HIF-1α and u-PFK2, while M2 macrophages are fueled by OXPHOS and have increased levels of Arg-1, AMPK and PFKFB1. M1 macrophages release pro-inflammatory cytokines such as IL-1β, while M2 macrophages are involved in the response to parasite infection, as well as in wound healing, and they release the anti-inflammatory cytokine IL-10. In fact, it is thought that a spectrum of macrophage activation exists, with different populations of macrophages exhibiting different inflammatory and metabolic phenotypes.
Mentions: Many of the processes that drive the glycolytic switch in M1 macrophages are downregulated in M2 macrophages (Figure 4). First, arginase 1 (Arg-1) is highly expressed in M2 macrophages, while iNOS expression is decreased93. M1 macrophages have increased levels of citrulline and the inflammatory mediator NO, while in M2 macrophages, arginine is preferentially metabolized to urea and ornithine94. Ornithine can be further metabolized to polyamines and proline. Schistosome eggs induce Arg-1 expression in infected mice, and the combination of IL-4 and IL-13 increases proline production by macrophages93. This increased proline production could contribute to granuloma formation and liver fibrosis in infected mice, as both of these are enhanced when proline synthesis is boosted93. However, there is also conflicting evidence suggesting that Arg-1-expressing macrophages suppress schistosome-induced fibrosis during chronic infection95. Interestingly, Arg-1 can be induced in classically activated macrophages by intracellular infection with mycobacteria, and functions in this context to suppress NO production96. M. tuberculosis-infected mice lacking Arg-1 expression in macrophages are better able to clear the bacteria96.

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