NR4A nuclear receptors in immunity and atherosclerosis

Hamers, Anouk A.J.; Hanna, Richard N.; Nowyhed, Heba; Hedrick, Catherine C.; Vries, Carlie J.M. de

doi:10.1097/mol.0b013e3283643eac

Cited by 67 publications

(61 citation statements)

References 30 publications

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“…Atherosclerosis may be considered a chronic inflammatory disease driven by macrophage activation in which Nur77 has an anti-inflammatory function (24,25). Nur77, along with its family members, was also shown to be important for thymic regulatory T cell development and immune homeostasis (16). Finally, peripheral eosinophils from patients with atopic dermatitis show increased Nur77 expression (26).…”

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confidence: 99%

“…Nur77 plays a pivotal role in the regulation of a wide range of biological processes, including cell proliferation, differentiation, and survival. Accumulating evidence suggests that Nur77 is implicated in the regulation of genes involved in metabolism, cancer, inflammation, and immunity and vascular disease (16)(17)(18)(19). In particular, Nur77 has been shown to have a protective function in restenosis and atherosclerosis (20,21).…”

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confidence: 99%

“…Nur77 is also known as NR4A1, TR3, or NGFI-B and is a member of the NR4A subfamily of nuclear receptors that are early response genes induced by diverse extracellular signals (16)(17)(18). Nur77 plays a pivotal role in the regulation of a wide range of biological processes, including cell proliferation, differentiation, and survival.…”

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confidence: 99%

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Nuclear Receptor Nur77 Attenuates Airway Inflammation in Mice by Suppressing NF-κB Activity in Lung Epithelial Cells

Kurakula

Vos

Logiantara

et al. 2015

The Journal of Immunology

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Allergic asthma is characterized by persistent chronic airway inflammation, which leads to mucus hypersecretion and airway hyperresponsiveness. Nuclear receptor Nur77 plays a pivotal role in distinct immune and inflammatory cells and is expressed in eosinophils and lung epithelium. However, the role of Nur77 in allergic airway inflammation has not been studied so far. In the present study, we determined the role of Nur77 in airway inflammation using a murine model of OVA-induced allergic airway inflammation. We found that OVA-challenged Nur77 knockout (KO) mice show significantly enhanced infiltration of inflammatory cells, including eosinophils and lymphocytes, and aggravated mucus production. The infiltration of macrophages is limited in this model and was similar in wild-type and Nur77 KO mice. Higher levels of Th2 cytokines were found in bronchoalveolar lavage fluid and draining lymph node cells of Nur77-KO mice, as well as increased serum IgG1 and IgG2a levels. Knockdown of Nur77 in human lung epithelial cells resulted in a marked increase in IκBα phosphorylation, corresponding with elevated NF-κB activity, whereas Nur77 overexpression decreased NF-κB activity. Consistently, Nur77 significantly decreased mRNA levels of inflammatory cytokines and Muc5ac expression and also attenuated mucus production in lung epithelial cells. To further corroborate these findings, we searched for association of single nucleotide polymorphisms in Nur77 gene with asthma and with the severity of bronchial hyperresponsiveness. We identified three Nur77 single nucleotide polymorphisms showing association with severity of bronchial hyperresponsiveness in asthma patients. Collectively, these findings support a protective role of Nur77 in OVA-induced airway inflammation and identify Nur77 as a novel therapeutic target for airway inflammation.

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Nuclear Receptor Nur77 Attenuates Airway Inflammation in Mice by Suppressing NF-κB Activity in Lung Epithelial Cells

Kurakula

Vos

Logiantara

et al. 2015

The Journal of Immunology

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“…NGFI-B (Nur77; NR4A1), NGFI-Bb (Nurr1; NR4A2), reduce whereas NOR-1 (NR4A3) exacerbates atherosclerotic vascular lesions in mice [55]. Targetting macrophage NGFI-B (Nur77) activation in macrophages either by pharmacological activation or overexpression reduces atherosclerosis in apoE knockout mice [56].…”

Section: Orphan/ Atypical Nuclear Receptorsmentioning

confidence: 99%

“…This family of nuclear receptors has clear roles in immune cell selection and development [55]. NGFI-B (Nur77; NR4A1), NGFI-Bb (Nurr1; NR4A2), reduce whereas NOR-1 (NR4A3) exacerbates atherosclerotic vascular lesions in mice [55].…”

Section: Orphan/ Atypical Nuclear Receptorsmentioning

confidence: 99%

Nuclear Receptors in Vascular Biology

Bishop‐Bailey

2015

Curr Atheroscler Rep

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Nuclear receptors sense a diverse group of steroids and hormones (estrogens, progesterone, androgens, glucocorticoid and mineralocorticoid), vitamins (A and D), lipid metabolites, carbohydrates and xenobiotics. In response to these diverse but critically important mediators, nuclear receptors regulate the homeostatic control of lipids, carbohydrate, cholesterol and xenobiotic drug metabolism, inflammation, cell differentiation and development, including vascular development. The nuclear receptor family is one of the most important groups of signaling molecules in the body, and as such represent some of the most important established and emerging clinical and therapeutic targets. This review will highlight some of the emerging trends in nuclear receptor biology related to vascular biology.3

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Transient downregulation of NR4A1 leads to impaired osteoblast differentiation through the TGF‐ß pathway, and Elesclomol (STA‐4783) rescues this phenotype

Muthurangan,

Elsafadi,

Siyal

et al. 2023

Cell Biochemistry & Function

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Bone formation is regulated by numerous factors, such as transcription factors, cytokines, and extracellular matrix molecules. Human hormone nuclear receptors (hHNR) are a family of ligand-regulated transcription factors that are activated by steroid hormones, such as estrogen and progesterone, and various lipid-soluble signals, including retinoic acid, oxysterols, and thyroid hormone. We found that an hHNR called NR4A1 was the most highly expressed after human MSC differentiation into osteoblasts by whole-genome microarray. NR4A1 knockout decreased the osteoblastic differentiation of hMSCs in terms of ALPL expression and key marker gene expression. Wholegenome microarray analysis further confirmed the decrease in key pathways when we knocked down NR4A1. Further studies with small molecule activators identified a novel molecule called Elesclomol (STA-4783), which could activate and enhance osteoblast differentiation. Elesclomol activation of hMSCs also induced the gene expression of NR4A1 and rescued the phenotype of NR4A1 KD. In addition, Elesclomol activated the TGF-ß pathway by regulating key marker genes. In conclusion, we first identified the role of NR4A1 in osteoblast differentiation and that Elesclomol is a positive regulator of NR4A1 through activation of the TGF-ß signalling pathway.

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NR4A nuclear receptors in immunity and atherosclerosis

Cited by 67 publications

References 30 publications

Nuclear Receptor Nur77 Attenuates Airway Inflammation in Mice by Suppressing NF-κB Activity in Lung Epithelial Cells

Nuclear Receptor Nur77 Attenuates Airway Inflammation in Mice by Suppressing NF-κB Activity in Lung Epithelial Cells

Nuclear Receptors in Vascular Biology

Transient downregulation of NR4A1 leads to impaired osteoblast differentiation through the TGF‐ß pathway, and Elesclomol (STA‐4783) rescues this phenotype

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