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, Mei; Yang, Jun J.; Chen, Ying; Vasiliou, Vasilis; Cassel, Teresa; Green, Douglas R.; Liu, Yusen; Fan, Teresa W.‐M.; Wang, Ruoning

doi:10.7554/elife.36158

Cited by 148 publications

(114 citation statements)

References 119 publications

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“…The balance between ROS generation and antioxidant capacity is necessary to ensures physiological levels of intracellular ROS and T cell-mediated immune response. Accordingly, excessive ROS generation in T cells will destroy the intracellular redox balance and leads to metabolism disorder and immune response dysfunction [30,31]. Here, we also observed markedly raised ROS level and decreased antioxidant enzyme activity of SOD, CAT and GSH-Px in the D-gal-treated group.…”

Section: Discussionsupporting

confidence: 59%

hPMSCs protects against aging-induced oxidative damage of CD4+ T cells through activating Akt-mediated Nrf2 antioxidant signaling

Xiong

Wang

Zhang

et al. 2020

Preprint

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Background: Mesenchymal stem cells (MSCs) was considered as regenerative therapeutic approach in both acute and chronic diseases. However, whether MSCs regulate the antioxidant metabolism of CD4+ T cells and weaken immunosenescence remains unclear. Here, we reported the protective effects of hPMSCs in aging-related CD4+ T cell senescence and identified the underlying mechanisms using a D-gal induced mouse aging model.Methods: In vivo study, 40 male C57BL/6 mice (8 weeks) were randomly divided into four groups: control group, D-gal group, hPMSC group and PBS group. In in vitro experiment, human naive CD4+ T (CD4CD45RA) cells were prepared using a naive CD4+ T cell isolation kit II and pretreated with the Akt inhibitor LY294002 and Nrf2 inhibitor ML385. Then, isolated naive CD4+ T cell were cocultured with hPMSCs for 72 h in the absence or presence of anti-CD3/CD28 Dynabeads and IL-2 as a mitogenic stimulus. Intracellular ROS changes were detected by flow cytometry. The activities of the antioxidant enzymes superoxide dismutase, glutathione peroxidase and catalase were measured by colorimetric analysis. The senescent T cells were detected SA-β-gal stain. The expression of aging related proteins were detected by Western blotting, RT-PCR and confocal microscopy.Results: We found that hPMSC treatment markedly decreased the ROS level, SA-β-gal positive cells number, senescence-associated secretory phenotype (IL-6 and OPN) expression and aging-related protein (P16 and P21) expression in senescent CD4+ T cells. Furthermore, hPMSC treatment effectively upregulated Nrf2 nuclear translocation and the expression of downstream target genes (HO-1, CAT, GCLC and NQO1) in senescent CD4+ T cells. Moreover, in vitro studies revealed that hPMSCs attenuated CD4+ T cell senescence by upregulating the Akt/GSK-3β/Fyn pathway to activate Nrf2 functions. Conversely, the antioxidant effects of hPMSCs were blocked by the Akt inhibitor LY294002 and Nrf2 inhibitor ML385 in senescent CD4+ T cells.Conclusions: Our results indicate that hPMSCs attenuate D-gal induced CD4+ T cell senescence by activating Nrf2-mediated antioxidant defenses and that upregulation of Nrf2 by hPMSCs is regulated via the Akt/GSK-3β/Fyn pathway.

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Section: Discussionsupporting

confidence: 59%

hPMSCs protects against aging-induced oxidative damage of CD4+ T cells through activating Akt-mediated Nrf2 antioxidant signaling

Xiong

Wang

Zhang

et al. 2020

Preprint

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“…17,66,[129][130][131][132][133][134][135] Another consequence of increased mitochondrial biogenesis is augmented serine-and folate-dependent one-carbon metabolism, which regulates the generation of the methyl-donor S-adenosylmethionine (SAM), as well as glutathione and nucleotides important for T cell activation. 124,[136][137][138][139][140] In T cells, the upregulation of one-carbon metabolism-associated enzymes requires mTORC1 activation, 66 which may be mediated by the mTORC1-dependent activation of ATF4. 141 In summary, mTOR activity coordinates transcriptional and post-transcriptional programming to mediate anabolic metabolism for control of T cell responses.…”

Section: Metabolic and Immunological Inputs For Mtorc1mentioning

confidence: 99%

Signaling networks in immunometabolism

Saravia¹,

Raynor²,

Chapman³

et al. 2020

Cell Res

163

136

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Adaptive immunity is essential for pathogen and tumor eradication, but may also trigger uncontrolled or pathological inflammation. T cell receptor, co-stimulatory and cytokine signals coordinately dictate specific signaling networks that trigger the activation and functional programming of T cells. In addition, cellular metabolism promotes T cell responses and is dynamically regulated through the interplay of serine/threonine kinases, immunological cues and nutrient signaling networks. In this review, we summarize the upstream regulators and signaling effectors of key serine/threonine kinase-mediated signaling networks, including PI3K-AGC kinases, mTOR and LKB1-AMPK pathways that regulate metabolism, especially in T cells. We also provide our perspectives about the pending questions and clinical applicability of immunometabolic signaling. Understanding the regulators and effectors of immunometabolic signaling networks may uncover therapeutic targets to modulate metabolic programming and T cell responses in human disease.

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“…GSH is an important endogenous antioxidant that has a prominent contribution against oxidative stress (Hartmann et al, 2017). Lian et al (2018) showed that glutamine improves the oxidative stress response induced by myocardial I/R by enhancing GSH synthesis. The study reported that the glutamine metabolism in rat heart is inhibited by I/R, and pretreatment with glutamine reduces I/R injury and MI area with I/R injury.…”

Section: Glutamine Improves Myocardial Ischemia-reperfusion Injury Wimentioning

confidence: 99%

Essential Role of Nonessential Amino Acid Glutamine in Atherosclerotic Cardiovascular Disease

Chen

Zhang

et al. 2020

DNA and Cell Biology

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Atherosclerosis is a major disease that seriously harms human health and is known as the ''number one killer'' in developed countries and the leading cause of death worldwide. Glutamine is the most abundant nonessential amino acid in the human blood that has multifaceted effects on the body. Recent studies showed that glutamine is negatively corrected with the progression of atherosclerotic lesions. In this review, we focused on the relationship of glutamine with macrophage polarization, nitrification stress, oxidative stress injury, myocardial ischemia-reperfusion injury, and therapeutic angiogenesis to review its roles in atherosclerotic cardiovascular disease.

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

Cited by 148 publications

References 119 publications

hPMSCs protects against aging-induced oxidative damage of CD4+ T cells through activating Akt-mediated Nrf2 antioxidant signaling

hPMSCs protects against aging-induced oxidative damage of CD4+ T cells through activating Akt-mediated Nrf2 antioxidant signaling

Signaling networks in immunometabolism

Essential Role of Nonessential Amino Acid Glutamine in Atherosclerotic Cardiovascular Disease

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