Foxo3a tempers excessive glutaminolysis in activated T cells to prevent fatal gut inflammation in the murine IL-10−/− model of colitis

Hajjar, Stephanie; Nathan, Nayanan; Joseph, Julie; Mottawea, Walid; Ariana, Ardeshir; Pyatibrat, Sergey; Harper, Mary‐Ellen; Alain, Tommy; Blais, Alexandre; Russell, Ryan C.; Sad, Subash

doi:10.1038/s41418-021-00876-y

Cited by 5 publications

(3 citation statements)

References 71 publications

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“…Thus, it is of great significance to fully understand the molecular principles of GSCs self-renewal maintenance. STAT3 signaling was found to be commonly activated in GBM, and abnormal activation of STAT3 is essential for sustaining the self-renewal and tumorigenic potential of GSCs [8,[27][28][29]. However, the tumorigenic effects of STAT3 and the downstream genes of STAT3 are not fully understood.…”

Section: Discussionmentioning

confidence: 99%

GALNT2 sustains glioma stem cells by promoting CD44 expression

Liu

Chen

et al. 2023

Aging

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Glioblastoma (GBM) is the most prevalent and malignant brain tumor and is highly resistant to currently available treatment. In this study, we reveal that polypeptide N-acetylgalactosaminyltransferase 5 (GALNT2) expression level was elevated in GBM, IDH1 wildtype glioma, and GBM stem cells (GSCs). GALNT2 increased expression correlated with GBM patients’ unfavorable clinical outcomes. Functionally, targeting GALNT2 blocks GSCs cell proliferation, self-renewal, and malignant invasion through repressing CD44 expression. Most importantly, we first provide evidence suggesting that STAT3 activates GALNT2 expression at the transcriptional level by directly binding to the GALNT2 promoter. Through a rational screening, we found a GALNT2 inhibitor that dramatically suppresses GSCs self-maintenance in vitro and in vivo . Collectively, we uncovered the critical function of GALNT2 in promoting GSCs self-maintenance and GBM progression and may provide a new potential drug for GBM clinical therapy.

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Section: Discussionmentioning

confidence: 99%

GALNT2 sustains glioma stem cells by promoting CD44 expression

Liu

Chen

et al. 2023

Aging

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“…GLS converts glutamine to glutamate to support the tricarboxylic acid cycle and redox and epigenetic reactions ( 15 ). Many researches proves that GLS antagonist inhibits the activation of T cells ( 15 , 51 , 55 , 56 ). But it remains unclear whether it works in T cell-mediated disease models.…”

Section: Discussionmentioning

confidence: 99%

Targeting Glutamine Metabolism Ameliorates Autoimmune Hepatitis via Inhibiting T Cell Activation and Differentiation

Yin

et al. 2022

Front. Immunol.

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BackgroundAutoimmune hepatitis (AIH) is mediated by a cascade of T cell-mediated events directed at liver cells and persistent inflammation within the liver can eventually result in liver cirrhosis. Targeting glutamine metabolism has an impact on T cell activation and differentiation. However, the effect of glutamine metabolism blocking upon AIH remains unknown. We use glutaminase antagonist 6-diazo-5-oxo-L-norleucine (DON) for in vitro assays and its prodrug 2-(2-amino-4-methylpentanamido)-DON (JHU083) for in vivo assays to investigate the potential therapeutic effect and molecular mechanism of glutamine metabolism blocking in an AIH murine model.MethodsAIH mice were treated with JHU083 or vehicle before concanavalin A (ConA) administration, and disease severity was examined. Then activation and differentiation [including Th1/Th17 cells and cytotoxic T lymphocytes (CTL)] of T cells from Vehicle-WT, JHU083-AIH and Vehicle-AIH mice were tested. Furthermore, in vitro T cell activation and differentiation were measured using separated splenocytes stimulated with ConA with or without DON. The activation and differentiation of T cells were tested using flow cytometry, qRT-PCR and ELISA. Phosphorylation level of mammalian target of rapamycin (mTOR) and 70 kDa ribosomal protein S6 kinase (P70S6K) were examined by western blotting.ResultsJHU083 and DON significantly suppressed the activation of T cells and inhibited the differentiation of Th1/Th17 cells and CTL in vivo and in vitro. Besides, we demonstrated that glutamine metabolism blocking inhibited T cells activation and differentiation through decreasing the mRNA expression of amino acid transporter solute carrier family 7 member 5 (SLC7A5) and mitigating the activation of mTOR signaling.ConclusionsWe proved that targeting glutamine metabolism represents a potential new treatment strategy for patients with AIH and other T cell-mediated disease. Mechanistically, we demonstrated that glutamine metabolism blocking inhibits T cells activation and suppresses the differentiation of Th1/Th17 cells and CTL.

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“…It has been suggested that excessive glutamine consumption may contribute to T cell activation. [89] Moreover, inflammatory T cell responses have been associated with increased glutamine uptake, and blocking amino acid transporters such as adaptor protein caspase-1 recruitment domain amino acid transporter-2 and SLC7A5 can impair the induction of helper T cell 1 and helper T cell 17 cells while weakening T cell activation. [90,91] Additionally, AKG can act as a regulator of CD4(+) T cell differentiation, promoting the differentiation of naïve CD4(+) T cells into TH1 cells rather than Treg cells.…”

Section: Inflammationmentioning

confidence: 99%

The essential role of glutamine metabolism in diabetic cardiomyopathy: A review

Zhang

2023

Medicine

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Diabetic cardiomyopathy (DCM) is a pathophysiological condition caused by diabetes mellitus and is the leading cause of diabetes mellitus-related mortality. The pathophysiology of DCM involves various processes, such as oxidative stress, inflammation, ferroptosis, and abnormal protein modification. New evidence indicates that dysfunction of glutamine (Gln) metabolism contributes to the pathogenesis of DCM by regulating these pathophysiological mechanisms. Gln is a conditionally essential amino acid in the human body, playing a vital role in maintaining cell function. Although the precise molecular mechanisms of Gln in DCM have yet to be fully elucidated, recent studies have shown that supplementing with Gln improves cardiac function in diabetic hearts. However, excessive Gln may worsen myocardial injury in DCM by generating a large amount of glutamates or increasing O-GlcNacylation. To highlight the potential therapeutic method targeting Gln metabolism and its downstream pathophysiological mechanisms, this article aims to review the regulatory function of Gln in the pathophysiological mechanisms of DCM.

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Foxo3a tempers excessive glutaminolysis in activated T cells to prevent fatal gut inflammation in the murine IL-10−/− model of colitis

Cited by 5 publications

References 71 publications

GALNT2 sustains glioma stem cells by promoting CD44 expression

GALNT2 sustains glioma stem cells by promoting CD44 expression

Targeting Glutamine Metabolism Ameliorates Autoimmune Hepatitis via Inhibiting T Cell Activation and Differentiation

The essential role of glutamine metabolism in diabetic cardiomyopathy: A review

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