Author response: Glutathione de novo synthesis but not recycling process coordinates with glutamine catabolism to control redox homeostasis and directs murine T cell differentiation

Lian, Gaojian; Gnanaprakasam, JN Rashida; Wang, Tingting; Wu, Ruohan; Chen, Xuyong; Liu, Lingling; Shen, Yuqing; Yang, Mao; Yang, Jun; Chen, Ying; Vasiliou, Vasilis; Cassel, Teresa; Green, Douglas R.; Liu, Yusen; Fan, Teresa W.‐M.; Wang, Ruoning

doi:10.7554/elife.36158.029

Cited by 4 publications

(4 citation statements)

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“…GSH synthesis by neurons requires 3 amino acids (Glu, cysteine, and glycine) and 2 ATP-dependent enzymatic steps (Aoyama et al, 2008). Initially, the transport of cysteine, an important substrate for the synthesis of GSH, is mediated by EAAC1 (Lee et al, 2020); then GCL catalyzes the conjugation of cysteine and Glu to form γ-glutamylcysteine (γ-GC), and finally GS catalyzes the combination of γ-GC with glycine to synthesize GSH (Yu et al, 1999;Lian et al, 2018). Using histopathology, we found that the expression of EAAC1 increased significantly at 6-12 h while GCLC and GS reached their peaks at 2-6 h and 6-12 h after HI injury, respectively, which corresponds with the process of GSH synthesis.…”

Section: The Relationship Of Naag and Gsh And Their Metabolic Processes With The Altered Number Of Neurons During Hi Injurymentioning

confidence: 99%

Self-Regulation of Cerebral Metabolism and Its Neuroprotective Effect After Hypoxic-Ischemic Injury: Evidence From 1H-MRS

Yang

Wang

2021

Front. Neuroanat.

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1H-MRS technology can be used to non-invasively detect the content of cerebral metabolites, to assess the severity of hypoxic-ischemic (HI) injury, and to predict the recovery of compromised neurological function. However, changes to the cerebral self-regulation process after HI are still unclear. This study investigated the changes in cerebral metabolites and the potential relationship with the number of neurons and neural stem/progenitor cells (NSPC) using 1H-MRS, and finally clarifies the self-regulation of cerebral metabolism and neuroprotection after HI injury. Newborn Yorkshire pigs (28 males, 1.0–1.5 kg) aged 3–5 days were used for the HI model in this study. The pigs were randomly divided into the HI group (n = 24) and the control group (n = 4), then the experimental group was subdivided according to different recovery time after HI into the following groups: 0–2 h (n = 4), 2–6 h (n = 4), 6–12 h (n = 4), 12–24 h (n = 4), 24–48 h (n = 4), and 48–72 h (n = 4). Following the HI timepoints, 1H-MRS scans were performed and processed using LCModel software, and brain tissue was immunohistochemically stained for Nestin and NeuN. Immunofluorescence staining of creatine phosphokinase-BB (CK-BB), N-acetylaspartylglutamate synthetase (NAAGS), glutamate carboxypeptidase II (GCP-II), glutamate-cysteine ligase catalytic subunit (GCLC), glutathione synthase (GS), and excitatory amino acid carrier 1 (EAAC1) was then performed. The 1H-MRS results showed that cerebral N-acetylaspartylglutamate (NAAG), glutathione (GSH), and creatine (Cr) content reached their peaks at 12–24 h, which was consistent with the recovery time of hippocampal NSPCs and neurons, indicating a potential neuroprotective effect of NAAG, GSH, and Cr after HI injury.

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Section: The Relationship Of Naag and Gsh And Their Metabolic Processes With The Altered Number Of Neurons During Hi Injurymentioning

confidence: 99%

Self-Regulation of Cerebral Metabolism and Its Neuroprotective Effect After Hypoxic-Ischemic Injury: Evidence From 1H-MRS

Yang

Wang

2021

Front. Neuroanat.

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“…In addition to glucose and fatty acids, cells also utilize glutamine and leucine amino acids, which play a vital role in Teff's differentiation. CD4 + T cells deprived of glutamine differentiate into Tregs in-vitro condition [67]; however, iTregs show less dependency on amino acids for their energy requirements [68]. Glutamine metabolism involves the influx of glutamine in the TCA-cycle in the form of α-ketoglutarate.…”

Section: Regulatory T Cells and Effector T Cells Metabolismmentioning

confidence: 99%

“…Glutamine metabolism involves the influx of glutamine in the TCA-cycle in the form of α-ketoglutarate. This intermediate encourages Th1 cell differentiation by enhancing the expression of the inflammatory transcription factor T-bet [28,68]. The deletion of neutral-amino-acid transporter genes (Slc7a5 and Slc1a5 (also known as ASCT2) reduce glutamine uptake, glucose metabolism, and overall Teffs differentiation, however, it does not affect the generation of iTregs [69,70].…”

Section: Regulatory T Cells and Effector T Cells Metabolismmentioning

confidence: 99%

Targeting T-cell immunometabolism during transplantation

Kazmi

Khan

Shamma

et al. 2020

Preprint

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The balance between the immune system and its metabolism is becoming an effective therapeutic alternative in various inflammatory diseases, including organ transplantation. The interaction between the immune and metabolic pathways play a critical role in dictating disease pathology and progression, and the differences in the bioenergetic demands between immune cells enable them to differentiate into effector and regulatory cells. Recent studies have suggested that changes in intracellular metabolic programs control T cell activation, proliferation and differentiation into T effector (Teffs) or T regulatory cells (Tregs), and metabolic differences between Tregs and Teffs can shift the balance toward a more specific immune tolerance in organ rejection. Pharmacological targeting of T cells metabolism affects the balance between effector and regulatory function of T cells.This therapeutic modulation are of great interest in cancer, autoimmunity, and organ transplantation. In this review, we discuss major metabolic pathways that influence the activation, proliferation and differentiation of Tregs, and also special emphasis on liver kinase B1 (LKB1) pathway that provide stability of Tregs. We also highlight how Tregs metabolic regulome and LKB1 signaling pathway relationship contribute to rescue organ transplants from associated injuries and chronic rejection.

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“…When GVHD occurs, the imbalance in redox metabolism markedly exacerbates the in ammatory response elicited and tissue damage caused therein; however, the GSH redox status contributes to the mitigation of target tissue damage in GVHD [12]. GSH is the main nonenzymatic antioxidant and plays a key role in maintaining ROS homeostasis during T cell activation and in regulating the metabolic reprogramming of Myc-dependent T cells, while GSH can also reduce the production of Th17 cells [13,14]. Similarly, a previous study has shown that the ratio of GSH/GSSG is reduced in GVHD patients and a GVHD mouse model, and the level of ROS in T cells is positively correlated with PD-1 expression.…”

Section: Introductionmentioning

confidence: 99%

HPMSCs Inhibit the Expression of PD-1 in CD4+IL-10+ T Cells and Mitigate liver Damage in a GVHD Mouse Model by Regulating the Cross-talk Between Nrf2 and NF-κB Signaling Pathway

Zhang

et al. 2021

Preprint

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Background: The activation of T cells and imbalanced redox metabolism enhances the development of graft-versus-host disease (GVHD). Human placenta-derived mesenchymal stromal cells (hPMSCs) can improve GVHD through regulating T cell responses. However, whether hPMSCs balance the redox metabolism of CD4+IL-10+ T cells and liver tissue and alleviate GVHD remains unclear. This study aimed to investigate the effect of hPMSC-mediated treatment of GVHD associated with CD4+IL-10+ T cell generation via control of redox metabolism and PD-1 expression and whether the Nrf2 and NF-κB signaling pathways were both involved in the process.Methods: A GVHD mouse model was induced using 6-8-week-old C57BL/6 and Balb/c mice, which were treated with hPMSCs. In order to observe whether hPMSCs affect the generation of CD4+IL-10+ T cells via control of redox metabolism and PD-1 expression, a CD4+IL-10+ T cell culture system was induced using human naive CD4+ T cells. The percentage of CD4+IL-10+ T cells and their PD-1 expression levels were determined in vivo and in vitro using flow cytometry, and Nrf2, HO-1, NQO1, GCLC, GCLM, and NF-κB levels were determined by western blotting, qRT-PCR, and immunofluorescence, respectively. Hematoxylin-eosin, Masson’s trichrome and periodic acid-Schiff staining methods were employed to analyze the changes in hepatic tissue. Results: A decreased activity of superoxide dismutase (SOD) and a proportion of CD4+IL-10+ T cells with increased PD-1 expression were observed in GVHD patients and the mouse model. Treatment with hPMSCs increased SOD activity and GCL and GSH levels in the GVHD mouse model. The percentage of CD4+IL-10+ T cells with decreased PD-1 expression, as well as Nrf2, HO-1, NQO1, GCLC, and GCLM levels, both in the GVHD mouse model and in the process of CD4+IL-10+ T cell generation, were also increased, but NF-κB phosphorylation and nuclear translocation were inhibited after treatment with hPMSCs, which was accompanied by improvement of hepatic histopathological changes.Conclusions: The findings suggested that hPMSC-mediated redox metabolism balance and decreased PD-1 expression in CD4+IL-10+ T cells were achieved by controlling the crosstalk between Nrf2 and NF-κB, which further provided evidence for application of hPMSC-mediated treatment of GVHD.

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Author response: Glutathione de novo synthesis but not recycling process coordinates with glutamine catabolism to control redox homeostasis and directs murine T cell differentiation

Cited by 4 publications

References 0 publications

Self-Regulation of Cerebral Metabolism and Its Neuroprotective Effect After Hypoxic-Ischemic Injury: Evidence From 1H-MRS

Self-Regulation of Cerebral Metabolism and Its Neuroprotective Effect After Hypoxic-Ischemic Injury: Evidence From 1H-MRS

Targeting T-cell immunometabolism during transplantation

HPMSCs Inhibit the Expression of PD-1 in CD4+IL-10+ T Cells and Mitigate liver Damage in a GVHD Mouse Model by Regulating the Cross-talk Between Nrf2 and NF-κB Signaling Pathway

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