Downregulation of BDH2 modulates iron homeostasis and promotes DNA demethylation in CD4 + T cells of systemic lupus erythematosus

Zhao, Ming; Li, Mengying; Gao, Xiaofei; Jia, Sujie; Gao, Keqin; Zhou, Yin; Zhang, Huihui; Huang, Yi; Wang, Jing; Wu, Haijing; Lu, Qianjin

doi:10.1016/j.clim.2017.11.002

Cited by 45 publications

(38 citation statements)

References 38 publications

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“…Moreover, increased intracellular bioavailable iron in CD4 + T cells has also been linked to the pathophysiology of systemic lupus erythematosus (SLE). Levels of intracellular iron were increased significantly in SLE CD4 + T cells compared to healthy controls and the researchers suggest a link between iron homeostasis and global DNA methylation status (Zhao et al, 2018), by which SLE T cells exhibit reduced DNA demethylation resulting in enhanced immune-related gene expression. Interestingly a link between intracellular iron levels and epigenetic programming has also been described to control B cell activation, proliferation and antibody responses at the level of H3K9 demethylation at the promoter region of the cell-cycle regulator, cyclin E1 (Jiang et al, 2019).…”

Section: T Cells and Ironmentioning

confidence: 99%

The Role of Iron Regulation in Immunometabolism and Immune-Related Disease

Cronin

Woolf

Weiss

et al. 2019

Front. Mol. Biosci.

213

196

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Immunometabolism explores how the intracellular metabolic pathways in immune cells can regulate their function under different micro-environmental and (patho-)-physiological conditions (Pearce, 2010; Buck et al., 2015; O'Neill and Pearce, 2016). In the last decade great advances have been made in studying and manipulating metabolic programs in immune cells. Immunometabolism has primarily focused on glycolysis, the TCA cycle and oxidative phosphorylation (OXPHOS) as well as free fatty acid synthesis and oxidation. These pathways are important for providing the energy needs of cell growth, membrane rigidity, cytokine production and proliferation. In this review, we will however, highlight the specific role of iron metabolism at the cellular and organismal level, as well as how the bioavailability of this metal orchestrates complex metabolic programs in immune cell homeostasis and inflammation. We will also discuss how dysregulation of iron metabolism contributes to alterations in the immune system and how these novel insights into iron regulation can be targeted to metabolically manipulate immune cell function under pathophysiological conditions, providing new therapeutic opportunities for autoimmunity and cancer.

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Section: T Cells and Ironmentioning

confidence: 99%

The Role of Iron Regulation in Immunometabolism and Immune-Related Disease

Cronin

Woolf

Weiss

et al. 2019

Front. Mol. Biosci.

213

196

View full text Add to dashboard Cite

show abstract

“…Previous studies reported that BDH2 could participate in the regulation of immune system cells, which may contribute to the DNA demethylation of CD4 + T cells in systemic lupus erythematosus and dysregulate intracellular iron in macrophages 13, 36. In neoplasm studies, BDH2 may influence the progression of acute myeloid leukemia and esophageal squamous cell carcinoma through the regulation of cell apoptosis 14, 15.…”

Section: Discussionmentioning

confidence: 99%

BDH2 is downregulated in hepatocellular carcinoma and acts as a tumor suppressor regulating cell apoptosis and autophagy

Liang¹,

Zhang²,

Li³

et al. 2019

J. Cancer

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BDH2 is a short-chain dehydrogenase/reductase family member involved in several biological and pathological processes, including the utilization of cytosolic ketone bodies, immunocyte regulation and tumor progression. In this study, we first revealed that BDH2 was downregulated in HCC tissues by qRT-PCR and immunohistochemistry analysis and that low BHD2 expression was significantly associated with poor overall survival, poor tumor differentiation, increased tumor size, venous invasion and an advanced BCLC stage. Moreover, the results of a univariate analysis and multivariate analysis revealed that BDH2 may be regarded as an independent prognostic marker. As a member of a gene family involved in ketone metabolism, BDH2 upregulated the level of β-HB in liver cells as well as the level of H3 histone acetylation. Functional analysis showed that BDH2 expression inhibited tumor cell growth, proliferation and migration. The results of the mechanistic analysis revealed that BDH2 induced mitochondrial apoptosis and inhibited autophagy through the unfolded protein response. Therefore, BDH2 may be a new HCC prognostic marker and a useful treatment target.

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“…An influence of iron on the immune system [reviewed recently by Cronin et al (12)] may also come into play in the context of SLE. Indeed, a recent study reported increased iron levels in CD4 + T cells of SLE patients which was associated with epigenetic changes leading to the upregulation of various genes related to autoimmunity (13). As such, dysregulation of iron homeostasis could contribute to kidney injury via a number of mechanisms.…”

Section: Introductionmentioning

confidence: 99%

Evidence of Renal Iron Accumulation in a Male Mouse Model of Lupus

et al. 2020

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Lupus nephritis represents a common and serious complication of the autoimmune disease Systemic Lupus Erythematosus (SLE). Clinical studies suggest that several proteins related to iron metabolism, including transferrin, serve as urinary biomarkers of lupus nephritis. We previously reported that in female NZBWF1 mice, a commonly used mouse model of SLE with a female sex bias, increased urinary transferrin excretion and renal iron accumulation occur around the onset of albuminuria. The current study investigated whether similar findings occur in male mice of a different mouse model of SLE, the MRL/lpr mouse. Two different cohorts were studied: MRL/lpr mice at an early, pre-albuminuric age (8 weeks), and after developing albuminuria (>100 mg/dL, confirmed by ELISA); age-matched MRL/MpJ control strain mice served for comparison. Urinary transferrin excretion was dramatically increased in the older, albuminuric MRL/lpr mice compared to the age-matched MRL/MpJ (P < 0.05), but there was no significant difference between strains at 8 weeks of age. Similarly, there were no significant differences between strains in renal cortical or outer medullary non-heme iron concentrations at 8 weeks. In the older, albuminuric MRL/lpr mice, renal cortical and outer medullary non-heme iron concentrations were significantly increased compared with age-matched MRL/MpJ mice, as was the expression of the iron storage protein ferritin (P < 0.01). Together, these data show that increased urinary transferrin excretion and renal tissue iron accumulation also occurs in albuminuric male MRL/lpr mice, suggesting that renal iron accumulation may be a feature of multiple mouse models of SLE.

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Downregulation of BDH2 modulates iron homeostasis and promotes DNA demethylation in CD4 + T cells of systemic lupus erythematosus

Cited by 45 publications

References 38 publications

The Role of Iron Regulation in Immunometabolism and Immune-Related Disease

The Role of Iron Regulation in Immunometabolism and Immune-Related Disease

BDH2 is downregulated in hepatocellular carcinoma and acts as a tumor suppressor regulating cell apoptosis and autophagy

Evidence of Renal Iron Accumulation in a Male Mouse Model of Lupus

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