Metabolic Controls on Epigenetic Reprogramming in Regulatory T Cells

Lü, Jingli; Liang, Yan; Meng, Haiyang; Zhang, Ailing; Zhao, Junjie; Zhang, Chengliang

doi:10.3389/fimmu.2021.728783

Cited by 11 publications

(11 citation statements)

References 134 publications

(208 reference statements)

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“…These SCFAs may activate Treg under the epithelium of the large intestine. 24,36 Based on this, a detailed investigation of the involvement of PHB in the intestinal microbiota will be necessary in the future.…”

Section: Discussionmentioning

confidence: 99%

“…The acetylation status of histones regulates FoxP3 activity. 36 Several reports indicate that 3-HB is an endogenous HDAC inhibitor implicated in intestinal epithelial integrity. 37 In addition, HDAC inhibitors SAHA and trichostatin A have been reported to have Treg-mediated anti-IBD effects, [37][38][39] suggesting that 3-HB produced by PHB degradation functions as an HDAC inhibitor in the intestinal tract.…”

Section: Discussionmentioning

confidence: 99%

“…In addition to its GPCR‐mediated action, 3‐HB inhibits histone deacetylases. The acetylation status of histones regulates FoxP3 activity 36 . Several reports indicate that 3‐HB is an endogenous HDAC inhibitor implicated in intestinal epithelial integrity 37 .…”

Section: Discussionmentioning

confidence: 99%

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The novel sustained 3‐hydroxybutyrate donor poly‐D ‐3‐hydroxybutyric acid prevents inflammatory bowel disease through upregulation of regulatory T‐cells

et al. 2022

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Inflammatory bowel disease (IBD) is a chronic persistent intestinal disorder, with ulcerative colitis and Crohn's disease being the most common. However, the physio-pathological development of IBD is still unknown. Therefore, research on the etiology and treatment of IBD has been conducted using a variety of approaches. Short-chain fatty acids such as 3-hydroxybutyrate (3-HB) are known to have various physiological activities. In particular, the production of 3-HB by the intestinal microflora is associated with the suppression of various inflammatory diseases. In this study, we investigated whether poly-D-3-hydroxybutyric acid (PHB), a polyester of 3-HB, is degraded by intestinal microbiota and works as a slow-release agent of 3-HB. Further, we examined whether PHB suppresses the pathogenesis of IBD models. As long as a PHB diet increased 3-HB concentrations in the feces and blood, PHB suppressed weight loss and histological inflammation in a dextran sulfate sodium-induced IBD model. Furthermore, PHB increased the accumulation of regulatory T cells in the rectum without affecting T cells in the spleen. These results indicate that PHB has potential applications in treating diseases related to the intestinal microbiota as a sustained 3-HB donor. We show for the first time that biodegradable polyester exhibits intestinal bacteria-mediated bioactivity toward IBD. The use of bioplastics, which are essential materials for How to cite this article: Suzuki R, Mishima M, Nagane M, et al. The novel sustained 3-hydroxybutyrate donor poly-D-3-hydroxybutyric acid prevents inflammatory bowel disease through upregulation of regulatory T-cells.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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The novel sustained 3‐hydroxybutyrate donor poly‐D ‐3‐hydroxybutyric acid prevents inflammatory bowel disease through upregulation of regulatory T‐cells

et al. 2022

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“…Tregs development depends on the key activities of Foxp3, the master-switch transcription factor (Piccirillo 2020 ). Altering the metabolic pathways and generation of metabolites can regulate Tregs (Lu et al 2021 ; W. Wang et al 2021a , b ). Based on the observations in colonic tissues, it was found that butyrate derived from commensal microbes induces Treg differentiation (Braun 2021 ; Furusawa et al 2013 ).…”

Section: Discussionmentioning

confidence: 99%

Dexmedetomidine alleviates acute lung injury by promoting Tregs differentiation via activation of AMPK/SIRT1 pathway

et al. 2022

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Objectives To explore the anti-inflammatory effect and the potential mechanism of dexmedetomidine in ARDS/ALI. Materials and Methods C57BL/6 mice and EL-4 cells were used in this research. The ALI model was established by CLP. The level of inflammatory cytokines in the lung and blood, the severity of lung injury, the expression of Foxp3, and the proportion of Tregs were detected before and after dexmedetomidine treatment. The expression of the AMPK/SIRT1 after dexmedetomidine treatment was detected in vivo and in vitro. After blocking the AMPK/SIRT1 pathway or depleting Tregs in vivo, the level of the inflammatory response, tissue injury, and Tregs differentiation were detected again to clarify the effect of dexmedetomidine. Results Dexmedetomidine significantly reduced systemic inflammation and lung injury in CLP mice. Dexmedetomidine enhanced the Foxp3 expression in the lungs and the frequency of Tregs in the spleen. Dexmedetomidine up-regulated the protein expression of p-AMPK and SIRT1 in lungs and EL-4 cells and facilitated the differentiation of naïve CD4 + T cells into Tregs in vitro. Meanwhile, DEX also increased the expression of Helios in Treg cells. Conclusions DEX could improve ARDS/ALI by facilitating the differentiation of Tregs from naïve CD4 + T cells via activating the AMPK/SIRT1 pathway.

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“…Inhibition of acetyl‐CoA carboxylase 1, the rate‐limiting enzyme for de novo fatty acid synthesis, increases the level of FAO and promotes the development of Treg cells [14]. Moreover, amino acid metabolism enzymes and intermediates are also important factors for the induction of Treg cells [15]. Kynurenine, the metabolite of tryptophan, can bind to aromatic hydrocarbon receptors on T cells and promote Treg cell differentiation [16].…”

Section: Introductionmentioning

confidence: 99%

Tetrandrine, an immunosuppressive alkaloid isolated from Steohania tetrandra S. Moore, induces the generation of Treg cells through enhancing fatty acid oxidation

et al. 2022

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Our previous studies have demonstrated that tetrandrine can induce the generation of regulatory T (Treg) cells in vitro and in vivo. But, the underlying mechanism of tetrandrine remains obscure. Naïve CD4+ T cells are isolated from the mesenteric lymph nodes of mice for the differentiation of Treg cells. Flow cytometry is used to detect the frequencies of Treg cells. Non‐targeted metabolomics analysis based on UHPLC‐QTOF/MS is performed to assess the intracellular metabolic profiles. ChIP‐PCR analysis is conducted to detect the level of H3K27ac at Foxp3 promoter and CNS regions. Tetrandrine treatment alters the metabolic profile of Treg cells, and pathway enrichment of differential metabolites mainly involves fatty acid oxidation (FAO). Tetrandrine promotes the mRNA expression of carnitine palmitoyl transferase‐1, and increases the level of acetyl coenzyme A (acetyl‐CoA) and the intracellular oxygen consumption rate. Either CPT1 inhibitor (etomoxir) or siRNA markedly diminishes the promotion of tetrandrine on Treg cell differentiation. Furthermore, tetrandrine enhances the acetylation of H3K27 in the promoter and CNS1 regions of Foxp3 through the acetyl‐CoA derived from FAO. In the mice with collagen‐induced arthritis, tetrandrine also induces Treg cell generation through FAO pathway. In addition, tetrandrine enhances the immunosuppressive function of Treg cells both in vitro and in vivo. The findings indicate that tetrandrine promotes Treg cell differentiation by enhancing FAO‐mediated Foxp3 acetylation, and the CPT1‐mediated FAO can serve as the target for the discovery of novel inducers of Treg cell generation.

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Metabolic Controls on Epigenetic Reprogramming in Regulatory T Cells

Cited by 11 publications

References 134 publications

The novel sustained 3‐hydroxybutyrate donor poly‐D ‐3‐hydroxybutyric acid prevents inflammatory bowel disease through upregulation of regulatory T‐cells

The novel sustained 3‐hydroxybutyrate donor poly‐D ‐3‐hydroxybutyric acid prevents inflammatory bowel disease through upregulation of regulatory T‐cells

Dexmedetomidine alleviates acute lung injury by promoting Tregs differentiation via activation of AMPK/SIRT1 pathway

Tetrandrine, an immunosuppressive alkaloid isolated from Steohania tetrandra S. Moore, induces the generation of Treg cells through enhancing fatty acid oxidation

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