The DNA Methylation Inhibitor Zebularine Controls CD4+ T Cell Mediated Intraocular Inflammation

Zou, Yanli; Hu, Xiao; Schewitz-Bowers, Lauren P; Stimpson, Madeleine L.; Li, Miao; Ge, Xiaofei; Liu, Yang; Li, Yan; Bible, Paul W.; Wen, Xiaofeng; Li, Jing Jing; Liu, Yizhi; Lee, Richard W.; Wei, Lai

doi:10.3389/fimmu.2019.01950

Cited by 16 publications

(12 citation statements)

References 32 publications

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“…Furthermore, IL-10 expression was investigated in both Th1 and Th17 cells suggesting a regulatory role [22]. Our study also demonstrated that the significant increase of Th17/Th1 phenotype in peak EAU in a monophasic mouse model was only detected in retinal tissues and not dLNs or peripheral blood [23], and suggests an important role of the tissue microenvironment in CD4 + T cell plasticity. Our detection of increased levels of intraocular Th17/Th1 cells in comparison to dLNs could be as a result of the local microenvironment within the eye, which contains a range of cytokines, notably TGF-ß [24].…”

Section: Discussionsupporting

confidence: 58%

Functionally distinct IFN‐γ⁺IL‐17A⁺ Th cells in experimental autoimmune uveitis: T‐cell heterogeneity, migration, and steroid response

et al. 2020

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Immunopathogenic roles for both Th1 (CD4 + IFN-γ +) and Th17 (CD4 + IL-17A +) cells have been demonstrated in experimental autoimmune uveitis (EAU). However, the role for Th17/Th1 (CD4 + T cells co-expressing IFN-γ and IL-17A) cells in EAU is not yet understood. Using interphotoreceptor retinoid-binding protein peptide-induced EAU in mice, we found increased levels of Th17/Th1 cells in EAU retinae (mean 9.6 ± 4.2%) and draining LNs (mean 8.4 ± 3.9%; p = 0.01) relative to controls. Topical dexamethasone treatment effectively reduced EAU severity and decreased retinal Th1 cells (p = 0.01), but had no impact on retinal Th17/Th1 or Th17 cells compared to saline controls. Using in vitro migration assays with mouse CNS endothelium, we demonstrated that Th17/Th1 cells were significantly increased within the migrated population relative to controls (mean 15.6 ± 9.5% vs. 1.9 ± 1.5%; p = 0.01). Chemokine receptor profiles of Th17/Th1 cells (CXCR3 and CCR6) did not change throughout the transendothelial migration process and were unaffected by dexamethasone treatment. These findings support a role for Th17/Th1 cells in EAU and their resistance to steroid inhibition suggests the importance of targeting both Th17 and Th17/Th1 cells for improving therapy.

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Section: Discussionsupporting

confidence: 58%

Functionally distinct IFN‐γ⁺IL‐17A⁺ Th cells in experimental autoimmune uveitis: T‐cell heterogeneity, migration, and steroid response

et al. 2020

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“…Similarly, research in mice models on azacitidine and decitabine function found that ZEB promoted Foxp3 expression and CpGs demethylation of the Tregs' upstream enhancer. In addition, human CD4 + ZEB-mediated cells had diminished INF-γ and IL-17A expression [83].…”

Section: Epigenetic Modifiers Of the Foxp3 Locusmentioning

confidence: 97%

Regulatory T Cells-Related Genes Are under DNA Methylation Influence

Piotrowska

Gliwiński

Trzonkowski

et al. 2021

IJMS

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Regulatory T cells (Tregs) exert a highly suppressive function in the immune system. Disturbances in their function predispose an individual to autoimmune dysregulation, with a predominance of the pro-inflammatory environment. Besides Foxp3, which is a master regulator of these cells, other genes (e.g., Il2ra, Ctla4, Tnfrsf18, Ikzf2, and Ikzf4) are also involved in Tregs development and function. Multidimensional Tregs suppression is determined by factors that are believed to be crucial in the action of Tregs-related genes. Among them, epigenetic changes, such as DNA methylation, tend to be widely studied over the past few years. DNA methylation acts as a repressive mark, leading to diminished gene expression. Given the role of increased CpG methylation upon Tregs imprinting and functional stability, alterations in the methylation pattern can cause an imbalance in the immune response. Due to the fact that epigenetic changes can be reversible, so-called epigenetic modifiers are broadly used in order to improve Tregs performance. In this review, we place emphasis on the role of DNA methylation of the genes that are key regulators of Tregs function. We also discuss disease settings that have an impact on the methylation status of Tregs and systematize the usefulness of epigenetic drugs as factors able to influence Tregs functions.

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“…Nonetheless, an analogue of DAC, named Zebularine, has been characterized and it is active per os [32,33]. However, although Zebularine has been show to downregulate autoimmune responses in experimental autoimmune uveitis [34], it has not reached the clinical development phase and complete preclinical development is required to be tested in humans.…”

Section: Discussionmentioning

confidence: 99%

Effects of Treatment with the Hypomethylating Agent 5-aza-2′-deoxycytidine in Murine Type II Collagen-Induced Arthritis

et al. 2019

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The emerging role of epigenetics in the pathogenesis of autoimmune diseases has recently attracted much interest on the possible use of epigenetic modulators for the prevention and treatment of these diseases. In particular, we and others have shown that drugs that inhibit DNA methylation, such as azacitidine (AZA) and decitabine (DAC), already used for the treatment of acute myeloid leukemia, exert powerful beneficial effects in rodent models of type 1 diabetes, multiple sclerosis, and Guillain Barrè syndrome. Along this line of research, we have presently studied the effects of DAC in a murine model of rheumatoid arthritis induced by type II collagen and have demonstrated that DAC administration was associated with a significant amelioration of the clinical condition, along with in vivo and ex vivo modification of the immunological profile of the so-treated mice, that exhibited a diminished production of Th1 and Th17 pro-inflammatory cytokines and reduction of anti-type II collagen autoantibodies.

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The DNA Methylation Inhibitor Zebularine Controls CD4+ T Cell Mediated Intraocular Inflammation

Cited by 16 publications

References 32 publications

Functionally distinct IFN‐γ⁺IL‐17A⁺ Th cells in experimental autoimmune uveitis: T‐cell heterogeneity, migration, and steroid response

Functionally distinct IFN‐γ⁺IL‐17A⁺ Th cells in experimental autoimmune uveitis: T‐cell heterogeneity, migration, and steroid response

Regulatory T Cells-Related Genes Are under DNA Methylation Influence

Effects of Treatment with the Hypomethylating Agent 5-aza-2′-deoxycytidine in Murine Type II Collagen-Induced Arthritis

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The DNA Methylation Inhibitor Zebularine Controls CD4+ T Cell Mediated Intraocular Inflammation

Cited by 16 publications

References 32 publications

Functionally distinct IFN‐γ+IL‐17A+ Th cells in experimental autoimmune uveitis: T‐cell heterogeneity, migration, and steroid response

Functionally distinct IFN‐γ+IL‐17A+ Th cells in experimental autoimmune uveitis: T‐cell heterogeneity, migration, and steroid response

Regulatory T Cells-Related Genes Are under DNA Methylation Influence

Effects of Treatment with the Hypomethylating Agent 5-aza-2′-deoxycytidine in Murine Type II Collagen-Induced Arthritis

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Product

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Functionally distinct IFN‐γ⁺IL‐17A⁺ Th cells in experimental autoimmune uveitis: T‐cell heterogeneity, migration, and steroid response

Functionally distinct IFN‐γ⁺IL‐17A⁺ Th cells in experimental autoimmune uveitis: T‐cell heterogeneity, migration, and steroid response