Aerobic glycolysis promotes T helper 1 cell differentiation through an epigenetic mechanism

Peng, Min; Yin, Na; Chhangawala, Sagar; Xu, Ke; Leslie, Christina; Li, Ming O.

doi:10.1126/science.aaf6284

Cited by 635 publications

(648 citation statements)

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“…Moreover LDH activity was increased in RA synovial tissues compared to healthy controls thus suggesting an increased glycolytic metabolism in the RA synovial joints [46]. The key role of LDH in promoting inflammation was also recently highlighted in the recent paper by Peng et al [47] where they identified that LDH-A is important to promote T-cell effector functions by increasing acetylation and IFN-γ transcription.Lactate transporters are becoming increasingly relevant in the pathogenesis of RA. Indeed, it has been recently found that monocarboxylate lactate transporter 4 (MCT4) is upregulated by RA synovial fibroblasts (RASF) compared to osteoarthritis SF.…”

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confidence: 84%

Lactate at the crossroads of metabolism, inflammation, and autoimmunity

et al. 2016

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For a long time after its discovery at the beginning of the 20th century, lactate was considered a waste product of cellular metabolism. Starting in the early '90s, however, lactate has begun to be recognized as an active molecule capable of modulating the immune response. Inflammatory sites, including in rheumatoid arthritis (RA) synovitis, are characterized by the accumulation of lactate, which is partly responsible for the establishment of an acidic environment. We have recently reported that T cells sense lactate via the expression of specific transporters, leading to inhibition of their motility. Importantly, this "stop migration signal" is dependent upon lactate's interference with intracellular metabolic pathways, specifically glycolysis. Furthermore, lactate promotes the switch of CD4 + T cells to an IL-17 + subset, and reduces the cytolytic capacity of CD8 + T cells. These phenomena might be responsible for the formation of ectopic lymphoid structures and autoantibody production in inflammatory sites such as in RA synovitis, Sjogren syndrome salivary glands, and multiple sclerosis plaques. Here, we review the roles of lactate in the modulation of the inflammatory immune response.Keywords: Arthritis r Inflammation r Lactate r Metabolism r T cells Crosstalk between immunity and metabolismThe immune system is constituted of a heterogeneous population of immune cells, which are able to respond to inflammatory stimuli upon switching from a quiescent to an activated status. These responses are tightly regulated by a wide range of cell type specific receptors and transcription factors. In immune cells this determines changes in the expression of large numbers of genes and results in the acquisition of new functions, such as the production of cytokines, lipid mediators and metabolites as well as the ability to proliferate, differentiate into specialized subtypes and migrate to target tissues. All such functions require the supply of nutrients into different metabolic pathways. In the last few yearsCorrespondence: Dr. Claudio Mauro e-mail: c.mauro@qmul.ac.uk there has been an increasing appreciation of how such metabolic pathways integrate with and in fact determine specific immune cell responses [1]. T-cell metabolism, inflammation, and autoimmunityIn the past few years, metabolism has been in the spotlight because of its pivotal role in disorders such as cancer as well as inflammatory and autoimmune diseases. Many studies have highlighted how cancer cells rely upon bioenergetic pathways to support their growth. As for cancer cells, immune cells also adapt their metabolic status as a consequence to changes in the external microenvironment (i.e. inflammation). T cells are key players of adaptive immunity and have high metabolic demand for their activation, proliferation, differentiation in specific cell subsets, and migration to target organs, while quiescent T cells rely mainly Alterations of this fine tuning between metabolism and immunity might lead to an unbalance between pro-and anti-inflammatory responses ...

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confidence: 84%

Lactate at the crossroads of metabolism, inflammation, and autoimmunity

et al. 2016

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“…In recent years, it has been shown a strong link between irreversible metabolic reactions, epigenetic patterns and gene expression patterns [13][14][15]34] as an evidence of a new and unified scenario. In this context, the phenomenological and thermodynamic approach could provide a solid basis for a new systemic conception.…”

Section: Discussionmentioning

confidence: 99%

“…In this context, the phenomenological and thermodynamic approach could provide a solid basis for a new systemic conception. In fact, it is plausible that living systems originate from a high value of the rate of entropy dissipation to reach a stationary minimum dissipation phase [14,15,42].…”

Section: Discussionmentioning

confidence: 99%

“…In addition, in the last years various studies have shown that metabolic patterns have a strong effect on genetic and epigenetic patterns and on chromatin structure [13][14][15]. As a result, there is a strict relationship between thermodynamic irreversibility and information expressed as the dialectic between Clausius entropy, Boltzmann entropy and informational Shannon entropy [16][17][18][19].…”

Section: Introductionmentioning

confidence: 99%

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Is an Entropy-Based Approach Suitable for an Understanding of the Metabolic Pathways of Fermentation and Respiration?

Zivieri

Pacini²

2017

Entropy

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Lactic fermentation and respiration are important metabolic pathways on which life is based. Here, the rate of entropy in a cell associated to fermentation and respiration processes in glucose catabolism of living systems is calculated. This is done for both internal and external heat and matter transport according to a thermodynamic approach based on Prigogine's formalism. It is shown that the rate of entropy associated to irreversible reactions in fermentation processes is higher than the corresponding one in respiration processes. Instead, this behaviour is reversed for diffusion of chemical species and for heat exchanges. The ratio between the rates of entropy associated to the two metabolic pathways has a space and time dependence for diffusion of chemical species and is invariant for heat and irreversible reactions. In both fermentation and respiration processes studied separately, the total entropy rate tends towards a minimum value fulfilling Prigogine's minimum dissipation principle and is in accordance with the second principle of thermodynamics. The applications of these results could be important for cancer detection and therapy.

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“…Mitochondrial acetyl-CoA cannot directly cross the mitochondrial membrane but, instead, is transferred to the cytosol via citrate export and conversion to acetyl-CoA by ATP citrate-lyase (ACLY) (6). ACLY has been shown to regulate histone acetylation levels and influence gene regulation in diverse mammalian cell types (19,21,(27)(28)(29), and histone acetylation is responsive to glucose availability in an ACLY-dependent manner (19,21,30). We have shown previously that Acly silencing impairs histone acetylation and expression of select genes such as Glut4 during 3T3-L1 adipocyte differentiation (18).…”

mentioning

confidence: 99%

Impact of a High-fat Diet on Tissue Acyl-CoA and Histone Acetylation Levels

Carrer

Parris

Trefely

et al. 2017

Journal of Biological Chemistry

143

116

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Edited by John M. DenuCellular metabolism dynamically regulates the epigenome via availability of the metabolite substrates of chromatin-modifying enzymes. The impact of diet on the metabolism-epigenome axis is poorly understood but could alter gene expression and influence metabolic health. ATP citrate-lyase produces acetyl-CoA in the nucleus and cytosol and regulates histone acetylation levels in many cell types. Consumption of a high-fat diet (HFD) results in suppression of ATP citrate-lyase levels in tissues such as adipose and liver, but the impact of diet on acetyl-CoA and histone acetylation in these tissues remains unknown. Here we examined the effects of HFD on levels of acyl-CoAs and histone acetylation in mouse white adipose tissue (WAT), liver, and pancreas. We report that mice consuming a HFD have reduced levels of acetyl-CoA and/or acetyl-CoA:CoA ratio in these tissues. In WAT and the pancreas, HFD also impacted the levels of histone acetylation; in particular, histone H3 lysine 23 acetylation was lower in HFD-fed mice. Genetic deletion of Acly in cultured adipocytes also suppressed acetyl-CoA and histone acetylation levels. In the liver, no significant effects on histone acetylation were observed with a HFD despite lower acetyl-CoA levels. Intriguingly, acetylation of several histone lysines correlated with the acetyl-CoA: (iso)butyryl-CoA ratio in liver. ButyrylCoA and isobutyryl-CoA interacted with the acetyltransferase P300/CBP-associated factor (PCAF) in liver lysates and inhibited its activity in vitro. This study thus provides evidence that diet can impact tissue acyl-CoA and histone acetylation levels and that acetyl-CoA abundance correlates with acetylation of specific histone lysines in WAT but not in the liver.

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Aerobic glycolysis promotes T helper 1 cell differentiation through an epigenetic mechanism

Cited by 635 publications

References 38 publications

Lactate at the crossroads of metabolism, inflammation, and autoimmunity

Lactate at the crossroads of metabolism, inflammation, and autoimmunity

Is an Entropy-Based Approach Suitable for an Understanding of the Metabolic Pathways of Fermentation and Respiration?

Impact of a High-fat Diet on Tissue Acyl-CoA and Histone Acetylation Levels

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