The nuclear receptor RORα exerts a bi-directional regulation of IL-6 in resting and reactive astrocytes

Journiac, Nathalie; Jolly, Sarah; Jarvis, Christopher; Gautheron, Vanessa; Rogard, Monique; Trembleau, Alain; Blondeau, Jean‐Paul; Mariani, Jean; Garabedian, Béatrice Vernet-der

doi:10.1073/pnas.0911782106

Cited by 67 publications

(55 citation statements)

References 42 publications

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“…Similar findings have also been mentioned in astrocytes, where Rev-erb␣ competes with ROR␣ for the up-regulation of IL6 in NF-B-dependent pathway (35). Rev-erb␣ competition with ROR␣ on IL6 gene promoter, however, has been shown to repress IL6 (35,36).…”

Section: Discussionsupporting

confidence: 67%

“…3C). Earlier studies have mentioned Rev-erb␣ in the bidirectional regulation of cytokine IL6 as well as in modulation of IL10, which implies that its role is as an equilibrist (35,36). Also, due to observed antimicrobial effects in Rev-erb␣-overexpressing cells, oxidative stress in MDMs overexpressing Rev-erb␣ was monitored by a DHR123 assay, which indicated significant change in reactive oxygen species (supplemental Fig.…”

Section: Rev-erb␣ Modulation Of Antimycobacterial Response Of Macrophmentioning

confidence: 99%

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Human IL10 Gene Repression by Rev-erbα Ameliorates Mycobacterium tuberculosis Clearance

Chandra

Mahajan

Saini

et al. 2013

Journal of Biological Chemistry

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Background: Transcriptional modulation of IL10, a cytokine that blocks phagolysosome maturation, is not well understood. Results: This study demonstrates human IL10 gene repression by direct binding of Rev-erb␣ on Rev-DR2 in the proximal promoter. Conclusion: Rev-erb␣ binds to IL10 proximal promoter, represses expression, and impedes Mycobacterium tuberculosis in human macrophages. Significance: This study provides rationale to target Rev-erb␣ as a therapeutic intervention that might support host defense in tuberculosis.Nuclear receptors modulate macrophage effector functions, which are imperative for clearance or survival of mycobacterial infection. The adopted orphan nuclear receptor Rev-erb␣ is a constitutive transcriptional repressor as it lacks AF2 domain and was earlier shown to be present in macrophages. In the present study, we highlight the differences in the relative subcellular localization of Rev-erb␣ in monocytes and macrophages. The nuclear localization of Rev-erb␣ in macrophages is subsequent to monocyte differentiation. Expression analysis of Rev-erb␣ elucidated it to be considerably more expressed in M1 phenotype in comparison with M2. Rev-erb␣ overexpression augments antimycobacterial properties of macrophage by keeping IL10 in a basal repressed state. Further, promoter analysis revealed that IL10 promoter harbors a Rev-erb␣ binding site exclusive to humans and higher order primates and not mouse, demonstrating a species barrier in its functionality. This direct gene repression is mediated by recruitment of co-repressors NCoR and HDAC3. In addition, our data elucidate that its overexpression reduced the survival of intracellular pathogen Mycobacterium tuberculosis by enhancing phagosome lysosome maturation, an event resulting from IL10 repression. Thus, these findings suggest that Rev-erb␣ bestows protection against mycobacterial infection by direct gene repression of IL10 and thus provide a novel target in modulating macrophage microbicidal properties.Macrophages are immune system sentinels with a major role to play in both innate and adaptive immunity. They are the key effectors in antimicrobial defense, atherogenesis, autoimmunity, and many other inflammatory diseases (1). Although the activation, function, classification, and plasticity of these cells have been studied extensively with regard to cellular signaling, the cytokine environment, and surface, cellular, or secretory markers, studies of the underlying molecular mechanism have mostly addressed NF-B (2). Similarly, modulation of macrophage function and alteration of disease pathology by small molecules such as heme, lipids, or drugs such as rifampicin are well understood at the translational level of the effectors (3, 4), but the transcriptional mechanism involving interactions of these ligands with transcriptional molecules and the resulting expression patterns have not been investigated.This study focuses on Rev-erb␣, an adopted orphan nuclear receptor that belongs to the steroid/thyroid hormone receptor superfamily and is a known ...

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Section: Discussionsupporting

confidence: 67%

Section: Rev-erb␣ Modulation Of Antimycobacterial Response Of Macrophmentioning

confidence: 99%

Human IL10 Gene Repression by Rev-erbα Ameliorates Mycobacterium tuberculosis Clearance

Chandra

Mahajan

Saini

et al. 2013

Journal of Biological Chemistry

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“…Thus, we surmise that clock dysfunction is in part responsible for increased proinflammatory gene expression in smokers and patients with COPD. This assertion is supported by the findings that core clock proteins (e.g., REV-ERBa) accumulate on the promoters of proinflammatory genes including IL-6, thereby inhibiting expression (5,7,38). Further study is required to determine if recruitment of core clock proteins and nuclear receptors to proinflammatory genes is altered in smokers and patients with COPD as compared with nonsmokers.…”

Section: Original Researchmentioning

confidence: 66%

Disruption of Sirtuin 1–Mediated Control of Circadian Molecular Clock and Inflammation in Chronic Obstructive Pulmonary Disease

Yao¹,

Sundar²,

Huang³

et al. 2015

Am J Respir Cell Mol Biol

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Chronic obstructive pulmonary disease (COPD) is the fourth most common cause of death, and it is characterized by abnormal inflammation and lung function decline. Although the circadian molecular clock regulates inflammatory responses, there is no information available regarding the impact of COPD on lung molecular clock function and its regulation by sirtuin 1 (SIRT1). We hypothesize that the molecular clock in the lungs is disrupted, leading to increased inflammatory responses in smokers and patients with COPD and its regulation by SIRT1. Lung tissues, peripheral blood mononuclear cells (PBMCs), and sputum cells were obtained from nonsmokers, smokers, and patients with COPD for measurement of core molecular clock proteins (BMAL1, CLOCK, PER1, PER2, and CRY1), clock-associated nuclear receptors (REV-ERBa, REV-ERBb, and RORa), and SIRT1 by immunohistochemistry, immunofluorescence, and immunoblot. PBMCs were treated with the SIRT1 activator SRT1720 followed by LPS treatment, and supernatant was collected at 6-hour intervals. Levels of IL-8, IL-6, and TNF-a released from PBMCs were determined by ELISA. Expression of BMAL1, PER2, CRY1, and REV-ERBa was reduced in PBMCs, sputum cells, and lung tissues from smokers and patients with COPD when compared with nonsmokers. SRT1720 treatment attenuated LPS-mediated reduction of BMAL1 and REV-ERBa in PBMCs from nonsmokers. Additionally, LPS differentially affected the timing and amplitude of cytokine (IL-8, IL-6, and TNF-a) release from PBMCs in nonsmokers, smokers, and patients with COPD. Moreover, SRT1720 was able to inhibit LPS-induced cytokine release from cultured PBMCs. In conclusion, disruption of the molecular clock due to SIRT1 reduction contributes to abnormal inflammatory response in smokers and patients with COPD.Keywords: circadian rhythm; SIRT1; REV-ERBa; BMAL1; smokers Clinical RelevanceAlthough the circadian clock regulates the inflammatory response, there is no information available regarding the impact of chronic obstructive pulmonary disease (COPD) on molecular clock function in peripheral tissues and its modulation by sirtuin 1 (SIRT1). We report here that clock proteins, including BMAL1 and REV-ERBa, are reduced in peripheral tissues from patients with COPD in part owing to SIRT1 reduction. LPS differently affects the timing and amplitude of cytokine release from peripheral blood mononuclear cells among nonsmokers, smokers, and patients with COPD. The SIRT1 activator SRT1720 is able to inhibit LPS-induced cytokine release in peripheral blood mononuclear cells. This has implications in the pathogenesis and pharmacological chronotherapy of COPD.

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“…One candidate is IL-6 (interleukin-6), a cytokine that can promote neuronal survival. We previously demonstrated that ROR␣ modulates its expression by astrocytes (Journiac et al, 2009). Alternatively, ROR␣-deficient astrocytes may secrete larger amounts of factors toxic to neurons, such as NO.…”

Section: Discussionmentioning

confidence: 99%

“…In the brain, ROR␣ is expressed in neurons in the cortex, cerebellum, inferior olivary nucleus, hippocampus, thalamus, hypothalamus, olfactory bulb, and retina (Ino, 2004). We also recently reported the nuclear expression of ROR␣ in astrocytes, particularly in the hippocampus, cortex, and cerebellum (Journiac et al, 2009). There is a natural mutant mouse for ROR␣, called staggerer, which carries a 122 bp deletion in the ligand-binding domain (LBD) of the Rora gene (Hamilton et al, 1996).…”

Section: Introductionmentioning

confidence: 99%

Cell-Autonomous and Non-Cell-Autonomous Neuroprotective Functions of RORα in Neurons and Astrocytes during Hypoxia

Jolly¹,

Journiac²,

Naudet³

et al. 2011

J. Neurosci.

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There is increasing evidence to suggest that the neuronal response to hypoxia is regulated through their interactions with astrocytes. However, the hypoxia-induced molecular mechanisms within astrocytes which influence neuronal death have yet to be characterized. In this study, we investigated the roles of the nuclear receptor ROR␣ (retinoid-related orphan receptor-␣) respectively in neurons and astrocytes during hypoxia using cultures and cocultures of neurons and astrocytes obtained from ROR␣-deficient mice. We found that loss of ROR␣ function in neuronal cultures increases neuronal death after hypoxia, suggesting a cell-autonomous neuroprotective effect of ROR␣. Moreover, wild-type neurons cocultured with ROR␣-deficient astrocytes are characterized by a higher death rate after hypoxia than neurons cocultured with wild-type astrocytes, suggesting that ROR␣ also has a non-cell-autonomous action. By using cocultures of neurons and astrocytes of different genotypes, we showed that this neuroprotective effect of ROR␣ in astrocytes is additive to its effect in neurons, and is mediated in part by cell-to-cell interactions between neurons and astrocytes. We also found that ROR␣ is upregulated by hypoxia in both neurons and astrocytes. Furthermore, our data showed that ROR␣ does not alter oxidative mechanisms during hypoxia but regulates hypoxic inducible factor 1␣ (HIF-1␣) expression, a major regulator of hypoxia sensing, in a cell-specific manner. Indeed, the neuroprotective function of ROR␣ in astrocytes correlates with a downregulation of HIF-1␣ selectively in these cells. Altogether, our results show that ROR␣ is a key molecular player in hypoxia, protecting neurons through its dual action in neurons and astrocytes.

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The nuclear receptor RORα exerts a bi-directional regulation of IL-6 in resting and reactive astrocytes

Cited by 67 publications

References 42 publications

Human IL10 Gene Repression by Rev-erbα Ameliorates Mycobacterium tuberculosis Clearance

Human IL10 Gene Repression by Rev-erbα Ameliorates Mycobacterium tuberculosis Clearance

Disruption of Sirtuin 1–Mediated Control of Circadian Molecular Clock and Inflammation in Chronic Obstructive Pulmonary Disease

Cell-Autonomous and Non-Cell-Autonomous Neuroprotective Functions of RORα in Neurons and Astrocytes during Hypoxia

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