NOR-1 modulates the inflammatory response of vascular smooth muscle cells by preventing NFκB activation

Calvayrac, Olivier; Rodríguez-Calvo, Ricardo; Martí-Pàmies, Íngrid; Alonso, Judith; Ferrán, Beatriz; Aguiló, Silvia; Crespo, Javier; Rodríguez‐Sinovas, Antonio; Rodrı́guez, Cristina; Martínez-González, José

doi:10.1016/j.yjmcc.2014.12.015

Cited by 40 publications

(32 citation statements)

References 49 publications

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“…Collectively, we describe how NR4A genes are regulated by NF-κB in order to feedback/limit downstream target gene expression. This study therefore expands and supports growing observations in several cell types deciphering this feedback regulatory loop, which is needed to control the magnitude of inflammatory responses (11, 12, 14, 19). …”

Section: Discussionsupporting

confidence: 84%

“…(9, 14)]. Second, NR4A receptors have been shown to be critical in regulating their appropriate expression during inflammatory responses by our group and others (3, 9, 10, 14, 19). …”

Section: Resultsmentioning

confidence: 88%

“…Analysis revealed that depletion of NR4A2 within this model results in further enhancement of MIP-3α expression with concurrent NF-κB/p65 binding to its promoter (14). Additionally, using vascular SMCs, it has recently been shown that overexpression of NR4A3 can attenuate LPS-driven MIP-3α production (19). Importantly, herein we reveal that NR4A2 and 3 can act as positive regulators of MIP-3α expression in human and murine myeloid cells during TLR4 or TNFα receptor stimulation, and furthermore, this regulation is governed by NF-κB activity.…”

Section: Discussionmentioning

confidence: 99%

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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: 84%

“…(9, 14)]. Second, NR4A receptors have been shown to be critical in regulating their appropriate expression during inflammatory responses by our group and others (3, 9, 10, 14, 19). …”

Section: Resultsmentioning

confidence: 88%

Section: Discussionmentioning

confidence: 99%

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NR4A Receptors Differentially Regulate NF-κB Signaling in Myeloid Cells

et al. 2017

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“…Nor1 overexpression induces endothelial cell activation, with increased expression of proadhesive molecules VCAM-1 (vascular cell adhesion molecule 1) and ICAM-1 (intercellular adhesion molecule 1), 25 findings that would be considered at odds with the findings of Yang et al 3 However, contrasting these reports that define Nor1 as proinflammatory in the vasculature, transgenic overexpression of Nor1 in mice attenuates the inflammatory response to lipopolysaccharide, reducing IκBα phosphorylation/degradation and inhibiting phosphorylation and nuclear translocation of NF-κB. 27 Taken together, the roles of the nuclear receptors, Nor1 and Nur77, in the vasculature are complex, often opposing, and undoubtedly dictated by context. Further complicating the picture is the fact that these NR4A members also variably exhibit tumor suppressor or oncogenic properties.…”

Section: Arterioscler Thromb Vasc Biol February 2016mentioning

confidence: 99%

A Nuclear Attack on Thrombosis and Inflammation

Conway

2016

ATVB

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“…Lentiviral overexpression of neuron-derived orphan receptor-1 (NOR-1) also significantly reduced LPS (100 ng/ml, for 24 h)-induced expression of cytokines (IL-1β, -6 and -8) and chemokines (MCP-1 and CCL20) in human vascular SMCs with a mechanism that NOR-1 impaired NF-κB-mediated transcriptional activation and interfered NF-κB signaling pathway in vascular SMCs, postulating a role for NOR-1 as a potentially relevant player in modulating vascular inflammation. 107 …”

Section: Introductionmentioning

confidence: 99%

Interaction between allergic asthma and atherosclerosis

Liu

Zhang

Shi

2016

Translational Research

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Prior studies have established an essential role of mast cells in allergic asthma and atherosclerosis. Mast cell deficiency or inactivation protects mice from allergen-induced airway hyper-responsiveness and diet-induced atherosclerosis, suggesting that mast cells share pathologic activities in both diseases. Allergic asthma and atherosclerosis are inflammatory diseases that contain similar sets of elevated numbers of inflammatory cells in addition to mast cells in the airway and arterial wall, such as macrophages, monocytes, T cells, eosinophils, and smooth muscle cells. Emerging evidence from experimental models and human studies points to a potential interaction between the two seemingly unrelated diseases. Patients or mice with allergic asthma have a high risk of developing atherosclerosis or vice versa, despite the fact that asthma is a Th2-oriented disease, whereas Th1 immunity promotes atherosclerosis. In addition to the preferred Th1/Th2 responses that may differentiate the two diseases, mast cells and many other inflammatory cells also contribute to their pathogenesis by much more than just T cell immunity. Here we summarize the different roles of airway and arterial wall inflammatory cells and vascular cells in asthma and atherosclerosis, and propose an interaction between the two diseases, although limited investigations are available to delineate the molecular and cellular mechanisms by which one disease increases the risk of the other. Results from mouse allergic asthma and atherosclerosis models and from human population studies lead to the hypothesis that patients with atherosclerosis may benefit from anti-asthmatic medications, or that the therapeutic regimens targeting atherosclerosis may also alleviate allergic asthma.

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NOR-1 modulates the inflammatory response of vascular smooth muscle cells by preventing NFκB activation

Cited by 40 publications

References 49 publications

NR4A Receptors Differentially Regulate NF-κB Signaling in Myeloid Cells

NR4A Receptors Differentially Regulate NF-κB Signaling in Myeloid Cells

A Nuclear Attack on Thrombosis and Inflammation

Interaction between allergic asthma and atherosclerosis

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