HIF1α–dependent glycolytic pathway orchestrates a metabolic checkpoint for the differentiation of TH17 and Treg cells

Shi, Lewis Zhichang; Wang, Ruoning; Huang, Gonghua; Vogel, Peter; Neale, Geoffrey; Green, Douglas R.; Chi, Hongbo

doi:10.1084/jem.20110278

Cited by 1,464 publications

(1,830 citation statements)

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“…It is now clear that acute and chronic inflammatory responses can add to the total tissue injury that occurs, making it important to identify how it is regulated. Complex interactions are occurring between inflammation and metabolism, and their importance is increasingly appreciated with the identification of mechanistic pathways (10,27,29). One aspect of this interrelationship is the change in metabolism that occurs with the initiation of inflammation.…”

Section: Discussionmentioning

confidence: 99%

Activation of N-methyl-d-aspartate receptor downregulates inflammasome activity and liver inflammation via a β-arrestin-2 pathway

Farooq

Hoque

Ouyang

et al. 2014

American Journal of Physiology-Gastrointestinal and Liver Physi

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Farooq A, Hoque R, Ouyang X, Farooq A, Ghani A, Ahsan K, Guerra M, Mehal WZ. Activation of N-methyl-D-aspartate receptor downregulates inflammasome activity and liver inflammation via a ␤-arrestin-2 pathway. Am J Physiol Gastrointest Liver Physiol 307: G732-G740, 2014. First published August 7, 2014; doi:10.1152/ajpgi.00073.2014.-Activation of the cytosolic inflammasome machinery is responsible for acute and chronic liver inflammation, but little is known about its regulation. The N-methyl-Daspartate (NMDA) receptor families are heterotetrameric ligand-gated ion channels that are activated by a range of metabolites, including aspartate, glutamate, and polyunsaturated fatty acids. In the brain NMDA receptors are present on neuronal and nonneuronal cells and regulate a diverse range of functions. We tested the role of the NMDA receptor and aspartate in inflammasome regulation in vitro and in models of acute hepatitis and pancreatitis. We demonstrate that the NMDA receptor is present on Kupffer cells, and their activation on primary mouse and human cells limits inflammasome activation by downregulating NOD-like receptor family, pyrin domain containing 3 and procaspase-1. The NMDA receptor pathway is active in vivo, limits injury in acute hepatitis, and can be therapeutically further activated by aspartate providing protection in acute inflammatory liver injury. Downregulation of inflammasome activation by NMDA occurs via a ␤-arrestin-2 NF-k␤ and JNK pathway and not via Ca 2ϩ mobilization. We have identified the NMDA receptor as a regulator of inflammasome activity in vitro and in vivo. This has identified a new area of immune regulation associated by metabolites that may be relevant in a diverse range of conditions, including nonalcoholic steatohepatitis and total parenteral nutrition-induced immune suppression.aspartate

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Section: Discussionmentioning

confidence: 99%

Activation of N-methyl-d-aspartate receptor downregulates inflammasome activity and liver inflammation via a β-arrestin-2 pathway

Farooq

Hoque

Ouyang

et al. 2014

American Journal of Physiology-Gastrointestinal and Liver Physi

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“…The transcription factor hypoxia-inducible factor 1α (HIF1α) is positively regulated by PI3K-AKT-mTOR signals 101,102 . HIF1α induces the expression of genes that are required for glycolysis when stabilized by low oxygen availability.…”

Section: Box 2 | Phenotypic Plasticity In Inflammatory and Regulatorymentioning

confidence: 99%

“…Indeed, deletion in T Reg cells of von Hippel-Lindau (VHL), an E3 ubiquitin ligase that targets HIF1α, increases HIF1α activity, leading to ectopic IFNγ production and reduced FOXP3 expression 103 . HIF1α has a particularly important role in T H 17 cell polarization, for which, in addition to promoting glycolysis, it directly induces the expression of RORγt and supports its function 102,104 . The transcriptional activity of HIF1α is also opposed by the transcriptional repressor BCL-6 (B cell lymphoma 6), which competes for binding to many of the same genes, preventing the induction of glycolytic genes that may be detrimental to the T FH cell programme 105 .…”

Section: Box 2 | Phenotypic Plasticity In Inflammatory and Regulatorymentioning

confidence: 99%

Harnessing the plasticity of CD4+ T cells to treat immune-mediated disease

2016

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| CD4 + T cells differentiate and acquire distinct functions to combat specific pathogens but can also adapt their functions in response to changing circumstances. Although this phenotypic plasticity can be potentially deleterious, driving immune pathology, it also provides important benefits that have led to its evolutionary preservation. Here, we review CD4 + T cell plasticity by examining the molecular mechanisms that regulate it -from the extracellular cues that initiate and drive cells towards varying phenotypes, to the cytosolic signalling cascades that decipher these cues and transmit them into the cell and to the nucleus, where these signals imprint specific gene expression programmes. By understanding how this functional flexibility is achieved, we may open doors to new therapeutic approaches that harness this property of T cells.

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“…Conversely, AMPK suppresses mTOR activity and promotes lipid oxidation (6,10). The balance between mTOR and AMPK signaling has a proven role in Teff and Treg lineage commitment, with mTOR and HIF1α promoting Teff and AMPK promoting Treg (6,(11)(12)(13)(14). Importantly, the mechanisms that coordinate T-cell metabolism of Teff and Treg remain poorly understood.…”

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confidence: 99%

Estrogen-related receptor-α is a metabolic regulator of effector T-cell activation and differentiation

Michalek¹,

Gerriets²,

Nichols³

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

192

189

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Stimulation of resting CD4 + T lymphocytes leads to rapid proliferation and differentiation into effector (Teff) or inducible regulatory (Treg) subsets with specific functions to promote or suppress immunity. Importantly, Teff and Treg use distinct metabolic programs to support subset specification, survival, and function. Here, we describe that the orphan nuclear receptor estrogen-related receptor-α (ERRα) regulates metabolic pathways critical for Teff. Resting CD4 + T cells expressed low levels of ERRα protein that increased on activation. ERRα deficiency reduced activated T-cell numbers in vivo and cytokine production in vitro but did not seem to modulate immunity through inhibition of activating signals or viability. Rather, ERRα broadly affected metabolic gene expression and glucose metabolism essential for Teff. In particular, up-regulation of Glut1 protein, glucose uptake, and mitochondrial processes were suppressed in activated ERRα −/− T cells and T cells treated with two chemically independent ERRα inhibitors or by shRNAi. Acute ERRα inhibition also blocked T-cell growth and proliferation. This defect appeared as a result of inadequate glucose metabolism, because provision of lipids, but not increased glucose uptake or pyruvate, rescued ATP levels and cell division. Additionally, we have shown that Treg requires lipid oxidation, whereas Teff uses glucose metabolism, and lipid addition selectively restored Tregbut not Teff-generation after acute ERRα inhibition. Furthermore, in vivo inhibition of ERRα reduced T-cell proliferation and Teff generation in both immunization and experimental autoimmune encephalomyelitis models. Thus, ERRα is a selective transcriptional regulator of Teff metabolism that may provide a metabolic means to modulate immunity. glycolysis | fatty acid | oxidative metabolism | mammalian target of rapamycin | AMPK

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HIF1α–dependent glycolytic pathway orchestrates a metabolic checkpoint for the differentiation of TH17 and Treg cells

Abstract: HIF1α induction by mTOR represents a metabolic checkpoint for the differentiation of TH17 and Treg cells.

Cited by 1,464 publications

References 35 publications

Activation of N-methyl-d-aspartate receptor downregulates inflammasome activity and liver inflammation via a β-arrestin-2 pathway

Activation of N-methyl-d-aspartate receptor downregulates inflammasome activity and liver inflammation via a β-arrestin-2 pathway

Harnessing the plasticity of CD4+ T cells to treat immune-mediated disease

Estrogen-related receptor-α is a metabolic regulator of effector T-cell activation and differentiation

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