Deficiency of Nuclear Receptor Nur77 Aggravates Mouse Experimental Colitis by Increased NFκB Activity in Macrophages

Hamers, Anouk A.J.; Dam, Laura van; Duarte, José; Vos, Mariska; Marinković, Goran; Tiel, Claudia M. van; Meijer, Sybren L.; Stalborch, Anne-Marieke D. van; Huveneers, Stephan; Velde, Anje A. te; Jonge, Wouter J. de; Vries, Carlie J.M. de

doi:10.1371/journal.pone.0133598

Cited by 65 publications

(71 citation statements)

References 80 publications

(102 reference statements)

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“…Within this study, we demonstrate that LPS and TNFα stimulation drives gene and protein secretion of chemokines MIP-3α and MCP-1 in primary and immortalized human and murine (LPS only) myeloid cells. We further identify NF-κB to be the upstream regulator of both chemokines within these conditions and cells consistent with previous studies in myeloid and other cell types (14, 26, 29, 30). Interestingly, we observed using depleted cells that NR4A2 and 3 were positive regulators of inflammatory-driven MIP-3α in human THP-1 cells and murine RAW264.7 macrophage cells (NR4A2 only), while repressors of MCP-1 as stated above.…”

Section: Discussionsupporting

confidence: 90%

NR4A Receptors Differentially Regulate NF-κB Signaling in Myeloid Cells

et al. 2017

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Dysregulation of inflammatory responses is a hallmark of multiple diseases such as atherosclerosis and rheumatoid arthritis. As constitutively active transcription factors, NR4A nuclear receptors function to control the magnitude of inflammatory responses and in chronic inflammatory disease can be protective or pathogenic. Within this study, we demonstrate that TLR4 stimulation using the endotoxin lipopolysaccharide (LPS) rapidly enhances NR4A1–3 expression in human and murine, primary and immortalized myeloid cells with concomitant gene transcription and protein secretion of MIP-3α, a central chemokine implicated in numerous pathologies. Deficiency of NR4A2 and NR4A3 in human and murine myeloid cells reveals that both receptors function as positive regulators of enhanced MIP-3α expression. In contrast, within the same cell types and conditions, altered NR4A activity leads to suppression of LPS-induced MCP-1 gene and protein expression. An equivalent pattern of inflammatory gene regulation is replicated in TNFα-treated myeloid cells. We show that NF-κB is the critical regulator of NR4A1–3, MIP-3α, and MCP-1 during TLR4 stimulation in myeloid cells and highlight a parallel mechanism whereby NR4A activity can repress or enhance NF-κB target gene expression simultaneously. Mechanistic insight reveals that NR4A2 does not require DNA-binding capacity in order to enhance or repress NF-κB target gene expression simultaneously and establishes a role for NF-κB family member Relb as a novel NR4A target gene involved in the positive regulation of MIP-3α. Thus, our data reveal a dynamic role for NR4A receptors concurrently enhancing and repressing NF-κB activity in myeloid cells leading to altered transcription of key inflammatory mediators.

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Section: Discussionsupporting

confidence: 90%

NR4A Receptors Differentially Regulate NF-κB Signaling in Myeloid Cells

et al. 2017

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“…Furthermore, Nur77 is known to regulate NF-jB and MAPKs pathways that contribute to the biological functions of Nur77 (Hamers et al 2015;Li et al 2015a;Shao et al 2016). In this study, we found that activation or overexpression of Nur77 inhibited the NF-jB activation, as evidenced by decreased transcriptional activity of NF-jB, decreased phosphorylation, and degradation of IjBa as well as the subsequent nuclear translocation of NF-jB p65 in LPS-activated microglia.…”

Section: Discussionsupporting

confidence: 48%

“…Furthermore, Nur77 is known to regulate NF‐κB and MAPKs pathways that contribute to the biological functions of Nur77 (Hamers et al . ; Li et al . ; Shao et al .…”

Section: Discussionmentioning

confidence: 99%

Activation of Nur77 in microglia attenuates proinflammatory mediators production and protects dopaminergic neurons from inflammation‐induced cell death

Liu

Yang

Zheng

et al. 2016

Journal of Neurochemistry

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Microglia-mediated neuroinflammation plays a critical role in the pathological development of Parkinson's disease (PD). Orphan nuclear receptor Nur77 (Nur77) is abundant in neurons, while its role in microglia-mediated neuroinflammation remains unclear. The present data demonstrated that the expression of Nur77 in microglia was reduced accompanied by microglia activation in response to lipopolysaccharide (LPS) in vitro and in experimental 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-PD mouse model. Nur77 over-expression or application of Nur77 agonist cytosporone B suppressed the expression of proinflammatory genes, such as inducible nitric oxide NOS, cyclooxygenase-2, IL-1β, and tumor necrosis factor-α in the activated microglia, while silenced Nur77 exaggerated the inflammatory responses in microglia. Moreover, activation of Nur77 suppressed the LPS-induced NF-κB activation which was partly dependent on p38 MAPK activity, since inhibition of p38 MAPK by SB203580 abolished the LPS-activated NF-κB in microglia. On the other hand, inhibition of p38 MAPK attenuated LPS-induced Nur77 reduction. Furthermore, in a microglia-conditioned cultured media system, Nur77 ameliorated the cytotoxicity to MN9D dopaminergic cells. Lastly, cytosporone B attenuated microglia activation and loss of dopaminergic neuron in the substantia nigra pars compacta (SNpc) of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-PD mouse model. Taken together, these findings revealed the first evidence that Nur77 was an important modulator in microglia function that associated with microglia-mediated dopaminergic neurotoxicity, and thus modulation of Nur77 may represent a potential novel target for treatment for neurodegenerative disease.

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“…Recent interest has focused on its potent anti-inflammatory effect in inflammatory diseases and cancer. Genetic studies have revealed a critical role of Nur77 in controlling the inflammatory responses, highlighted by its protective function in atherosclerosis (Hamers et al, 2012; Hanna et al, 2012), obesity (Perez-Sieira et al, 2013), diabetes (Chao et al, 2009), asthma (Kurakula et al, 2015), arthritis (De Silva et al, 2005), and inflammatory bowel disease (Hamers et al, 2015; Wu et al, 2016). …”

Section: Introductionmentioning

confidence: 99%

Celastrol-Induced Nur77 Interaction with TRAF2 Alleviates Inflammation by Promoting Mitochondrial Ubiquitination and Autophagy

et al. 2017

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SUMMARY Mitochondria play an integral role in cell death, autophagy, immunity, and inflammation. We previously showed that Nur77, an orphan nuclear receptor, induces apoptosis by targeting mitochondria. Here, we report that celastrol, a potent anti-inflammatory pentacyclic triterpene, binds Nur77 to inhibit inflammation and induce autophagy in a Nur77-dependent manner. Celastrol promotes Nur77 translocation from the nucleus to mitochondria, where it interacts with tumor necrosis factor receptor-associated factor 2 (TRAF2), a scaffold protein and E3 ubiquitin ligase important for inflammatory signaling. The interaction is mediated by an LxxLL motif in TRAF2 and results not only in the inhibition of TRAF2 ubiquitination but also in Lys63-linked Nur77 ubiquitination. Under inflammatory conditions, ubiquitinated Nur77 resides at mitochondria, rendering them sensitive to autophagy, an event involving Nur77 interaction with p62/SQSTM1. Together, our results identify Nur77 as a critical intracellular target for celastrol and unravel a mechanism of Nur77-dependent clearance of inflamed mitochondria to alleviate inflammation.

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Deficiency of Nuclear Receptor Nur77 Aggravates Mouse Experimental Colitis by Increased NFκB Activity in Macrophages

Cited by 65 publications

References 80 publications

NR4A Receptors Differentially Regulate NF-κB Signaling in Myeloid Cells

NR4A Receptors Differentially Regulate NF-κB Signaling in Myeloid Cells

Activation of Nur77 in microglia attenuates proinflammatory mediators production and protects dopaminergic neurons from inflammation‐induced cell death

Celastrol-Induced Nur77 Interaction with TRAF2 Alleviates Inflammation by Promoting Mitochondrial Ubiquitination and Autophagy

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