Orphan nuclear receptor Nur77 Inhibits Oxidized LDL-induced differentiation of RAW264.7 murine macrophage cell line into dendritic like cells

Hu, Liuhua; Yu, Ying; Jin, Shuxuan; Nie, Peng; Cai, Zhaohua; Cui, Mingli; Sun, Shiqun; Xiao, Haifeng; Shao, Qing; Shen, Linghong; He, Ben

doi:10.1186/s12865-014-0054-z

Cited by 6 publications

(7 citation statements)

References 25 publications

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“…Similar analysis of NRs in BMDCs treated with TGF‐β followed by LPS treatment further revealed some members of NR superfamily that were commonly regulated between different studied DC populations. Given that of these Vdr, Nr3c1, Nr4a1, Nr4a3, and Nr1h3, already have a reported role in DCs , we speculate that other commonly regulated NRs might also be having a plausible function in DCs. Another category of NRs included those members that were constitutively expressed in immature, immunogenic, and tolerogenic DCs.…”

Section: Discussionmentioning

confidence: 82%

“…Any disruption of this functional heterogeneity results in a dysregulated T‐cell immune response, leading to various pathophysiological conditions such as autoimmunity and cancer. Activation of few NR members has been shown to decide the fate of the DC phenotype ; however, a comprehensive study to identify the full set of NRs expressed in functional phenotypes of DCs has never been delineated before. Our study has extended the knowledge of NRs in DC functional heterogeneity.…”

Section: Discussionmentioning

confidence: 99%

“…On the contrary, Lxr, Rara, and Rxr induce immunogenicity in DCs by enhancing NF‐κB signaling . Among the Nr4a subfamily of orphan NRs, which consists of Nr4a1, Nr4a2, and Nr4a3, it has been suggested that Nr4a3 regulates apoptosis in DCs , while Nr4a1 might have a role to play in its differentiation . It is known that ligation of TLRs with their respective ligands induces Nr4a2 expression in DCs and macrophages , and that Nr4a2 modulates T‐cell responses during inflammatory responses.…”

Section: Introductionmentioning

confidence: 99%

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Nuclear receptor expression atlas in BMDCs: Nr4a2 restricts immunogenicity of BMDCs and impedes EAE

2016

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The nuclear receptor (NR) superfamily of transcription factors regulates various key aspects of physiological processes; however, their role(s) in immune cells' function are just beginning to unravel. Although few NRs have been shown to be critical for dendritic cell (DC) function, a lack of knowledge about their complete representation in DCs has limited the ability to harness their full potential. Here, we performed a comprehensive NR expression profiling and identified the key members of NR superfamily being expressed in immature, immunogenic, and tolerogenic DCs. Comparative analysis revealed discrete changes in the expression of various NRs among the studied DC subtypes, indicating a likely role in the modulation of DC functionality. Next, we characterized Nr4a2, a member of orphan NR family, and found that it suppresses the activation of bone marrow derived dendritic cells triggered by LPS. Overexpression and knockdown of Nr4a2 demonstrated that Nr4a2 orchestrates the expression of immunoregulatory genes, hence inducing a tolerogenic phenotype in bone marrow derived dendritic cells. Furthermore, we also found that Nr4a2 provides protection from EAE by promoting an increase in Treg cells, while limiting effector T cells. Our findings suggest a previously unidentified role for Nr4a2 as a regulator of DC tolerogenicity and demonstrate its potential as therapeutic target in DC-associated pathophysiologies. Keywords: Dendritic cells EAE Immune tolerance Nr4a2 Nuclear receptors Treg cellsAdditional supporting information may be found in the online version of this article at the publisher's web-site IntroductionDendritic cells (DCs) are indispensable immune sentinels that bridge the innate and adaptive immune responses. They have been primarily looked upon as inducers of immunity-immunogenic DCs; however, there is a growing body of evidence to support another facet of their function in induction and maintenance of tolerance-tolerogenic DCs. The phenotypic characteristics distinguishing these two functional DC phenotypes, immunogenic or tolerogenic, have begun to unravel. [1,9]. Interestingly, many of these modulators are known to be able to exert their effects through the members of nuclear receptor (NR) superfamily, which comprises 49 members in mice and 48 in humans.The NR superfamily comprises ligand-sensitive transcription factors that regulate various metabolic, developmental, homeostatic, and other physiological processes by modulating the expression of target genes [10,11]. NRs have been classified into three categories depending upon the nature of their ligands: (i) endocrine NRs that mediate the effects of endocrine hormones, (ii) orphan NRs whose regulatory ligands have not yet been identified, and (iii) adopted orphan NRs that were originally identified as orphan NRs, but were subsequently found to bind dietary lipids as their ligands [12,13]. Unlike other transcription factors, NRs are exceptionally promising therapeutic targets in biomedicine, because of their druggable potential. Consequently, NRs ...

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Section: Discussionmentioning

confidence: 82%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Nuclear receptor expression atlas in BMDCs: Nr4a2 restricts immunogenicity of BMDCs and impedes EAE

2016

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“…Oxidized low-density lipoprotein (oxLDL) induces mature macrophages to differentiate into dendritic cells and induces Nur77 expression in vascular cells. However, when Nur77 is overexpressed in RAW264.7 murine macrophages, differentiation into dendritic cells is inhibited in the presence of oxLDL [ 75 ]. This comes back to the key point that Nur77 functions are heavily dependent on cellular context, so it is possible for Nur77 to have opposing functions in different tissues and cell types.…”

Section: Discussionmentioning

confidence: 99%

Regulation of Nuclear Receptor Nur77 by miR-124

et al. 2016

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The nuclear receptor Nur77 is commonly upregulated in adult cancers and has oncogenic functions. Nur77 is an immediate-early response gene that acts as a transcription factor to promote proliferation and protect cells from apoptosis. Conversely, Nur77 can translocate to the mitochondria and induce apoptosis upon treatment with various cytotoxic agents. Because Nur77 is upregulated in cancer and may have a role in cancer progression, it is of interest to understand the mechanism controlling its expression. MicroRNAs (miRNAs) are responsible for inhibiting translation of their target genes by binding to the 3ʹUTR and either degrading the mRNA or preventing it from being translated into protein, thereby making these non-coding endogenous RNAs vital regulators of every cellular process. Several miRNAs have been predicted to target Nur77; however, strong evidence showing the regulation of Nur77 by any miRNA is lacking. In this study, we used a luciferase reporter assay containing the 3ʹUTR of Nur77 to screen 296 miRNAs and found that miR-124, which is the most abundant miRNA in the brain and has a role in promoting neuronal differentiation, caused the greatest reduction in luciferase activity. Interestingly, we discovered an inverse relationship in Daoy medulloblastoma cells and undifferentiated granule neuron precursors in which Nur77 is upregulated and miR-124 is downregulated. Exogenous expression to further elevate Nur77 levels in Daoy cells increased proliferation and viability, but knocking down Nur77 via siRNA resulted in the opposite phenotype. Importantly, exogenous expression of miR-124 reduced Nur77 expression, cell viability, proliferation, and tumor spheroid size in 3D culture. In all, we have discovered miR-124 to be downregulated in instances of medulloblastoma in which Nur77 is upregulated, resulting in a proliferative state that abets cancer progression. This study provides evidence for increasing miR-124 expression as a potential therapy for cancers with elevated levels of Nur77.

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“…Oxidized low-density lipoprotein (oxLDL) induces mature macrophages to differentiate into dendritic cells and induces NR4A1 expression in vascular cells. However, when NR4A1 is overexpressed in RAW264.7 murine macrophages, differentiation into dendritic cells is inhibited in the presence of oxLDL [499]. This comes back to the key point that NR4A1 functions are heavily dependent on cellular context, so it is possible for NR4A1 to have opposing functions in different tissues and cell types.…”

Section: Regulation Of Nr4a1 By Mirnas In Cancermentioning

confidence: 99%

The Roles of Nuclear Receptor NR4A1 in Cancer Cell Proliferation and Skeletal Muscle Differentiation

Farmer¹

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Orphan nuclear receptor Nur77 Inhibits Oxidized LDL-induced differentiation of RAW264.7 murine macrophage cell line into dendritic like cells

Cited by 6 publications

References 25 publications

Nuclear receptor expression atlas in BMDCs: Nr4a2 restricts immunogenicity of BMDCs and impedes EAE

Nuclear receptor expression atlas in BMDCs: Nr4a2 restricts immunogenicity of BMDCs and impedes EAE

Regulation of Nuclear Receptor Nur77 by miR-124

The Roles of Nuclear Receptor NR4A1 in Cancer Cell Proliferation and Skeletal Muscle Differentiation

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