Oxidative Stress and Inflammation Modulate Rev-erbα Signaling in the Neonatal Lung and Affect Circadian Rhythmicity

Guang, Yang; Wright, Clyde J.; Hinson, Maurice; Fernando, Amal P.; Sengupta, Shaon; Biswas, Chhanda; La, Ping; Dennery, Phyllis A.

doi:10.1089/ars.2013.5539

Cited by 71 publications

(65 citation statements)

References 78 publications

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“…The heme receptor REV-ERBα, encoded by Nr1d1, regulates the expression of genes involved in circadian rhythms [13, 14] metabolism [2, 3, 15] and inflammatory responses [16–19]. REV-ERBα and RORα provide stability and precision the timing of the molecular clock [20].…”

Section: Discussionmentioning

confidence: 99%

The nuclear receptor and clock gene REV-ERBα regulates cigarette smoke-induced lung inflammation

Sundar

Rashid

Sellix

et al. 2017

Biochemical and Biophysical Research Communications

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REV-ERBα is a nuclear heme receptor, transcriptional repressor and critical component of the molecular clock that drives daily rhythms of metabolism. Evidence reveals that REV-ERBα also plays an important regulatory role in clock-dependent lung physiology and inflammatory responses. We hypothesize that cigarette smoke (CS) exposure influences REV-ERBα abundance in the lungs, facilitating a pro-inflammatory phenotype. To determine the impact of REV-ERBα activation in the CS-induced inflammatory response we treated primary human small airway epithelial cells (SAECs) with CS extract (CSE) or lipopolysaccharide (LPS) in the absence or presence of pre-treatment with the REV-ERBα agonist GSK 4112. We also exposed adult C57BL/6J (WT) and Rev-erbα global KO mice to CS (10 and 30 days) and measured pro-inflammatory cytokine release. Our data reveal that pre-treatment with GSK 4112 reduced CSE/LPS induced pro-inflammatory cytokines release from both SAECs and mouse lung fibroblasts (MLFs). Furthermore, REV-ERBα KO mice show a greater inflammatory response to 10 and 30 days of CS, including increased neutrophil lung influx, pro-inflammatory cytokine (IL-6, MCP-1 and KC) release, and pro-senescence marker (p16) when compared to WT mice. These data demonstrate that REV-ERBα is a critical regulator of CS-induced lung inflammatory responses.

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Section: Discussionmentioning

confidence: 99%

The nuclear receptor and clock gene REV-ERBα regulates cigarette smoke-induced lung inflammation

Sundar

Rashid

Sellix

et al. 2017

Biochemical and Biophysical Research Communications

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“…Neonatal mouse lung fibroblasts (MLG) were obtained from American Type Culture Collection (Manassas, VA, USA) and maintained as described(24). …”

Section: Methodsmentioning

confidence: 99%

“…In addition to regulation of the clock, Rev-erbα also targets a large number of genes involved in metabolism and cell survival (15, 21–23). We have previously shown that Rev-erbα is regulated by oxidative stress and inflammation (24). However, the role of Rev-erbα in responding to the environmental insults, such as oxidative stress is not known.…”

Section: Introductionmentioning

confidence: 99%

The circadian gene Rev-erbα improves cellular bioenergetics and provides preconditioning for protection against oxidative stress

Sengupta

Guang

O‘Donnell

et al. 2016

Free Radical Biology and Medicine

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Diurnal oscillations in the expression of antioxidant genes imply that protection against oxidative stress is circadian-gated. We hypothesized that stabilization of the core circadian gene Rev-erbα (Nr1d1) improves cellular bioenergetics and protects against nutrient deprivation and oxidative stress. Compared to WT, mouse lung fibroblasts (MLG) stably transfected with a degradation resistant Rev-erbα (Ser55/59 to Asp; hence referred to as SD) had 40% higher protein content, 1.5-fold higher mitochondrial area (confocal microscopy), doubled oxidative phosphorylation by high-resolution respirometry (Oroboros) and were resistant to glucose deprivation for 24h. This resulted from a 4-fold reduction in mitophagy (L3CB co-localized with MitoTracker Red) vs WT. Although PGC1α protein expression was comparable between SD and WT MLG cells, the role of mitochondrial biogenesis in explaining increased mitochondrial mass in SD cells was less clear. Embryonic fibroblasts (MEF) from C57Bl/6-SD transgenic mice, had a 9-fold induction of FoxO1 mRNA and increased mRNA of downstream antioxidant targets heme oxygenase-1 (HO-1), Mn superoxide dismutase and catalase (1.5, 2 fold and 2 fold respectively) vs WT. This allowed the SD cells to survive 1h incubation with 500 μM H2O2 as well as 24hrs of exposure to 95% O2 and remain attached whereas most WT cells did not. These observations establish a mechanistic link between the metabolic functions of Rev-erbα with mitochondrial homeostasis and protection against oxidative stress.

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“…It has been shown that REV-ERBa binds to nuclear factor kappa B (NF-kB) (RelA/p65) and can activate NF-kB-dependent transcription. Transcription factors activator protein 1 (AP-1) and NF-kB share unique sequences that overlap consensus sequences from Rev-erb a promoters, suggesting a role for REV-ERBa in oxidative stress and/or inflammation (18). The impact of molecular clock dysfunction, particularly as it relates to lung pathophysiology and inflammatory responses, has been investigated in mice bearing loss-of-function clock gene mutations.…”

Section: Molecular Clock Dysfunction and Immune-inflammatory Responsesmentioning

confidence: 99%

Circadian Clock–Coupled Lung Cellular and Molecular Functions in Chronic Airway Diseases

Sundar¹,

Yao²,

Sellix

et al. 2015

Am J Respir Cell Mol Biol

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Airway diseases are associated with abnormal circadian rhythms of lung function, reflected in daily changes of airway caliber, airway resistance, respiratory symptoms, and abnormal immune-inflammatory responses. Circadian rhythms are generated at the cellular level by an autoregulatory feedback loop of interlocked transcription factors collectively referred to as clock genes. The molecular clock is altered by cigarette smoke, LPS, and bacterial and viral infections in mouse and human lungs and in patients with chronic airway diseases. Stressmediated post-translational modification of molecular clock proteins, brain and muscle aryl hydrocarbon receptor nuclear translocator-like 1 (BMAL1) and PERIOD 2, is associated with a reduction in the activity/ level of the deacetylase sirtuin 1 (SIRT1). Similarly, the levels of the nuclear receptor REV-ERBa and retinoic acid receptor-related orphan receptor a (ROR a), critical regulators of Bmal1 expression, are altered by environmental stresses. Molecular clock dysfunction is implicated in immune and inflammatory responses, DNA damage response, and cellular senescence. The molecular clock in the lung also regulates the timing of glucocorticoid sensitivity and phasic responsiveness to inflammation. Herein, we review our current understanding of clock-controlled cellular and molecular functions in the lungs, the impact of clock dysfunction in chronic airway disease, and the response of the pulmonary clock to different environmental perturbations.Furthermore, we discuss the evidence for candidate signaling pathways, such as the SIRT1-BMAL1-REV-ERBa axis, as novel targets for chronopharmacological management of chronic airway diseases.

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Oxidative Stress and Inflammation Modulate Rev-erbα Signaling in the Neonatal Lung and Affect Circadian Rhythmicity

Cited by 71 publications

References 78 publications

The nuclear receptor and clock gene REV-ERBα regulates cigarette smoke-induced lung inflammation

The nuclear receptor and clock gene REV-ERBα regulates cigarette smoke-induced lung inflammation

The circadian gene Rev-erbα improves cellular bioenergetics and provides preconditioning for protection against oxidative stress

Circadian Clock–Coupled Lung Cellular and Molecular Functions in Chronic Airway Diseases

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