The Role of Phase II Antioxidant Enzymes in Protecting Memory T Cells from Spontaneous Apoptosis in Young and Old Mice

Kim, Hyon-Jeen; Nel, André E.

doi:10.4049/jimmunol.175.5.2948

Cited by 49 publications

(42 citation statements)

References 87 publications

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“…As Kawai et al reported in inflammatory bone destructive diseases such as periodontitis, a major source of RANKL is from the infiltrating lymphocytes [31]. Although we have not tested the effects of 7R-ETGE peptide on RANKL expression in lymphocytes, some reports mentioned the possibility of developing anti-inflammatory therapeutic targeting of Nrf2 [32,33]. These reports suggest the possibility of the attenuation of RANKL expression in osteoclastogenesis supporting cells by 7R-ETGE peptide.…”

Section: Discussionmentioning

confidence: 74%

Nuclear Nrf2 Induction by Protein Transduction Attenuates Osteoclastogenesis

Kanzaki

Shinohara

Kajiya

et al. 2014

Free Radical Biology and Medicine

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It has been reported that reactive oxygen species (ROS) play a role as intracellular signaling molecules in RANKL stimulation. Previously we demonstrated that induction of cytoprotective enzyme expression by Nrf2-gene transfer successfully ameliorated RANKL-dependent osteoclastogenesis. In the present study, we hypothesized that Nrf2 activation by inhibiting ubiquitination and degradation of Nrf2 by ETGE-peptide would induce Nrf2-dependent cytoprotective enzyme expression, attenuate ROS signaling, and thereby inhibit RANKL-dependent osteoclastogenesis. ETGE-peptide containing a cell-permeable sequence (seven consecutive arginine; 7R-ETGE) was applied to a mouse macrophage cell-line RAW 264.7 cell or a primary macrophage culture. ETGE-peptide prevents Keap1 from binding to Nrf2. Nrf2 nuclear translocation and Nrf2-dependent cytoprotective enzyme induction was observed. The effects of 7R-ETGE on RANKL-dependent induction of intracellular ROS levels and osteoclastogenesis were examined. Finally, the protective effect of 7R-ETGE on RANKL-mediated bone destruction was investigated in mice. 7R-ETGE dose-dependently induced nuclear Nrf2, followed by the induction of cytoprotective enzyme expression at both the gene and protein level. 7R-ETGE inhibited upregulation of intracellular ROS levels by RANKL stimulation, and osteoclastogenesis was attenuated. Of particular interest was that local injection of 7R-ETGE ameliorated RANKL-mediated bone destruction. Local induction of nuclear Nrf2 by protein transduction is a potential novel therapeutic target for bone destruction diseases such as periodontitis and rheumatoid arthritis.

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Section: Discussionmentioning

confidence: 74%

Nuclear Nrf2 Induction by Protein Transduction Attenuates Osteoclastogenesis

Kanzaki

Shinohara

Kajiya

et al. 2014

Free Radical Biology and Medicine

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“…ROS thus constitute both a survival and differentiation signal for T cells, as also described for stem cells (9). Of note, EM CD4 + T cells possess more cell-intrinsic antioxidant mechanisms, and are characterized by lower steady-state ROS levels than are naive cells (31). This may protect these cells from high levels of exogenous ROS encountered in inflamed environments.…”

Section: Discussionmentioning

confidence: 98%

The Immune-Metabolic Basis of Effector Memory CD4+ T Cell Function under Hypoxic Conditions

Dimeloe

Mehling

Frick

et al. 2016

The Journal of Immunology

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Effector memory (EM) CD4+ T cells recirculate between normoxic blood and hypoxic tissues to screen for cognate Ag. How mitochondria of these cells, shuttling between normoxia and hypoxia, maintain bioenergetic efficiency and stably uphold antiapoptotic features is unknown. In this study, we found that human EM CD4+ T cells had greater spare respiratory capacity (SRC) than did naive counterparts, which was immediately accessed under hypoxia. Consequently, hypoxic EM cells maintained ATP levels, survived and migrated better than did hypoxic naive cells, and hypoxia did not impair their capacity to produce IFN-γ. EM CD4+ T cells also had more abundant cytosolic GAPDH and increased glycolytic reserve. In contrast to SRC, glycolytic reserve was not tapped under hypoxic conditions, and, under hypoxia, glucose metabolism contributed similarly to ATP production in naive and EM cells. However, both under normoxic and hypoxic conditions, glucose was critical for EM CD4+ T cell survival. Mechanistically, in the absence of glycolysis, mitochondrial membrane potential (ΔΨm) of EM cells declined and intrinsic apoptosis was triggered. Restoring pyruvate levels, the end product of glycolysis, preserved ΔΨm and prevented apoptosis. Furthermore, reconstitution of reactive oxygen species (ROS), whose production depends on ΔΨm, also rescued viability, whereas scavenging mitochondrial ROS exacerbated apoptosis. Rapid access of SRC in hypoxia, linked with built-in, oxygen-resistant glycolytic reserve that functionally insulates ΔΨm and mitochondrial ROS production from oxygen tension changes, provides an immune-metabolic basis supporting survival, migration, and function of EM CD4+ T cells in normoxic and hypoxic conditions.

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“…Naive T cells are more susceptible to ROS than memory T cells. Along these lines naive T cells where shown to have lower levels of the endogenous antioxidant glutathione (53,54).…”

Section: Discussionmentioning

confidence: 99%

Age-Associated Decline in Effective Immune Synapse Formation of CD4+ T Cells Is Reversed by Vitamin E Supplementation

Marko

Ahmed

Bunnell

et al. 2007

The Journal of Immunology

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Aging is associated with reduced IL-2 production and T cell proliferation. Vitamin E supplementation, in aged animals and humans, increases cell division and IL-2 production by naive T cells. The immune synapse forms at the site of contact between a T cell and an APC and participates in T cell activation. We evaluated whether vitamin E affects the redistribution of signaling proteins to the immune synapse. Purified CD4+ T cells, from the spleens of young and old mice, were treated with vitamin E before stimulation with a surrogate APC expressing anti-CD3. Using confocal fluorescent microscopy, we observed that CD4+ T cells from old mice were significantly less likely to recruit signaling proteins to the immune synapse than cells from young mice. Vitamin E increased the percentage of old CD4+ T cells capable of forming an effective immune synapse. Similar results were found following in vivo supplementation with vitamin E. When compared with memory cells, naive T cells from aged mice were more defective in immune synapse formation and were more responsive to vitamin E supplementation. These data show, for the first time, that vitamin E significantly improves age-related early T cell signaling events in naive CD4+ T cells.

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The Role of Phase II Antioxidant Enzymes in Protecting Memory T Cells from Spontaneous Apoptosis in Young and Old Mice

Cited by 49 publications

References 87 publications

Nuclear Nrf2 Induction by Protein Transduction Attenuates Osteoclastogenesis

Nuclear Nrf2 Induction by Protein Transduction Attenuates Osteoclastogenesis

The Immune-Metabolic Basis of Effector Memory CD4+ T Cell Function under Hypoxic Conditions

Age-Associated Decline in Effective Immune Synapse Formation of CD4+ T Cells Is Reversed by Vitamin E Supplementation

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