Superoxide Dismutase 3 Controls the Activation and Differentiation of CD4+T Cells

Agrahari, Gaurav; Sah, Shrawan Kumar; Bang, Chul Hwan; Kim, Yeong Ho; Kim, Taeyoon

doi:10.3389/fimmu.2021.628117

Cited by 13 publications

(7 citation statements)

References 59 publications

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“…The present results are consistent with the concept that SOD3 inhibits inflammation by targeting the NF-κB pathway [ 49 , 53 , 54 , 55 , 56 ], potentially by inhibiting IκB phosphorylation. IκB proteins inhibit NF-κB translocation into the nucleus, an inhibitory mechanism overturned by IκB phosphorylation (catalyzed by the IKK complex) [ 14 ].…”

Section: Discussionsupporting

confidence: 92%

Superoxide Dismutase-3 Downregulates Laminin α5 Expression in Tumor Endothelial Cells via the Inhibition of Nuclear Factor Kappa B Signaling

Carmona-Rodríguez

Martínez-Rey

Martín-González

et al. 2022

Cancers

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The balance between laminin isoforms containing the α5 or the α4 chain in the endothelial basement membrane determines the site of leukocyte diapedesis under inflammatory conditions. Extracellular superoxide dismutase (SOD3) induces laminin α4 expression in tumor blood vessels, which is associated with enhanced intratumor T cell infiltration in primary human cancers. We show now that SOD3 overexpression in neoplastic and endothelial cells (ECs) reduces laminin α5 in tumor blood vessels. SOD3 represses the laminin α5 gene (LAMA5), but LAMA5 expression is not changed in SOD1-overexpressing cells. Transcriptomic analyses revealed SOD3 overexpression to change the transcription of 1682 genes in ECs, with the canonical and non-canonical NF-κB pathways as the major SOD3 targets. Indeed, SOD3 reduced the transcription of well-known NF-κB target genes as well as NF-κB-driven promoter activity in ECs stimulated with tumor necrosis factor (TNF)-α, an NF-κB signaling inducer. SOD3 inhibited the phosphorylation and degradation of IκBα (nuclear factor of the kappa light polypeptide gene enhancer in B-cells inhibitor alpha), an NF-κB inhibitor. Finally, TNF-α was found to be a transcriptional activator of LAMA5 but not of LAMA4; LAMA5 induction was prevented by SOD3. In conclusion, SOD3 is a major regulator of laminin balance in the basement membrane of tumor ECs, with potential implications for immune cell infiltration into tumors.

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Section: Discussionsupporting

confidence: 92%

Superoxide Dismutase-3 Downregulates Laminin α5 Expression in Tumor Endothelial Cells via the Inhibition of Nuclear Factor Kappa B Signaling

Carmona-Rodríguez

Martínez-Rey

Martín-González

et al. 2022

Cancers

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“…Several studies have proven that SOD3 can protect tissues from oxidative stress [ 7 , 8 ]. SOD3 has been demonstrated to attenuate excessive inflammation and modulate cytokine responses in chronic inflammation [ 9 , 10 , 11 ]. Moreover, previous studies by Mañes group have demonstrated that SOD3 is involved in the regulation of cell barrier function [ 12 , 13 ].…”

Section: Introductionmentioning

confidence: 99%

Superoxide Dismutase 3-Transduced Mesenchymal Stem Cells Preserve Epithelial Tight Junction Barrier in Murine Colitis and Attenuate Inflammatory Damage in Epithelial Organoids

Tak

Kim

Ham

et al. 2021

IJMS

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Superoxide dismutase 3 (SOD3), also known as extracellular superoxide dismutase, is an enzyme that scavenges reactive oxygen species (ROS). It has been reported that SOD3 exerts anti-inflammatory abilities in several immune disorders. However, the effect of SOD3 and the underlying mechanism in inflammatory bowel disease (IBD) have not been uncovered. Therefore, in the present study, we investigated whether SOD3 can protect intestinal cells or organoids from inflammation-mediated epithelial damage. Cells or mice were treated with SOD3 protein or SOD3-transduced mesenchymal stem cells (MSCs). Caco-2 cells or intestinal organoids stimulated with pro-inflammatory cytokines were used to evaluate the protective effect of SOD3 on epithelial junctional integrity. Dextran sulfate sodium (DSS)-induced colitis mice received SOD3 or SOD3-transduced MSCs (SOD3-MSCs), and were assessed for severity of disease and junctional protein expression. The activation of the mitogen-activated protein kinase (MAPK) pathway and elevated expression of cytokine-encoding genes decreased in TNF-α-treated Caco-2 cells or DSS-induced colitis mice when treated with SOD3 or SOD3-MSCs. Moreover, the SOD3 supply preserved the expression of tight junction (ZO-1, occludin) or adherence junction (E-cadherin) proteins when inflammation was induced. SOD3 also exerted a protective effect against cytokine- or ROS-mediated damage to intestinal organoids. These results indicate that SOD3 can effectively alleviate enteritis symptoms by maintaining the integrity of epithelial junctions and regulating inflammatory- and oxidative stress.

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“…An increase in expression could be beneficial by decreasing reactive oxygen species production as it was described in CD4 + T cells during the acute phase of Trypanosoma cruzi infection early during T cell expansion (54). Similar to SOD3, SOD2 could also control the activation and differentiation of CD4+ T cells (55). From this study, we showed that miR-150 regulates SOD2 and both mouse and human SOD2 are listed on TargetScan as a possible direct targets for miR-150 but with only 1 putative 7mer binding site, suggesting a very weak interaction.…”

Section: Discussionmentioning

confidence: 92%

Antigen-specific downregulation of miR-150 in CD4 T cells promotes cell survival

et al. 2023

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MicroRNA-150 (miR-150) has been shown to play a general role in the immune system, but very little is known about its role on CD4+ T cell responses. During T cell responses against superantigen Staphylococcal Enterotoxin A, miR-150 expression was down-regulated in antigen-specific CD4+ T cells but up-regulated in CD8+ T cells. CD4+ and CD8+ T cell clonal expansion was greater in miR-150-KO mice than in WT mice, but miR-150 selectively repressed IL-2 production in CD4+ T cells. Transcriptome analysis of CD4+ T cells demonstrated that apoptosis and mTOR pathways were highly enriched in the absence of miR-150. Mechanistic studies confirmed that miR-150 promoted apoptosis specifically in antigen-specific CD4+ T cells, but not in bystander CD4+ nor in CD8+ T cells. Furthermore, inhibition of mTOR-linked mitochondrial superoxidedismutase-2 increased apoptosis in miR-150-/- antigen-specific CD4+ T. Thus, miR-150 impacts CD4+ T cell helper activity by attenuating IL-2 production along with clonal expansion, and suppresses superoxidedismutase to promote apoptosis.

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Superoxide Dismutase 3 Controls the Activation and Differentiation of CD4+T Cells

Cited by 13 publications

References 59 publications

Superoxide Dismutase-3 Downregulates Laminin α5 Expression in Tumor Endothelial Cells via the Inhibition of Nuclear Factor Kappa B Signaling

Superoxide Dismutase-3 Downregulates Laminin α5 Expression in Tumor Endothelial Cells via the Inhibition of Nuclear Factor Kappa B Signaling

Superoxide Dismutase 3-Transduced Mesenchymal Stem Cells Preserve Epithelial Tight Junction Barrier in Murine Colitis and Attenuate Inflammatory Damage in Epithelial Organoids

Antigen-specific downregulation of miR-150 in CD4 T cells promotes cell survival

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