Direct and Indirect Suppression of Interleukin-6 Gene Expression in Murine Macrophages by Nuclear Orphan Receptor REV-ERB<i>α</i>

Sato, Shogo; Sakurai, Takeshi; Ogasawara, Jun; Shirato, Ken; Ishibashi, Yoshinaga; Oh‐ishi, Shuji; Imaizumi, Kazunori; Haga, Shukoh; Hitomi, Yoshiaki; Izawa, Tetsuya; Ohira, Yoshinobu; Ohno, Hideki; Kizaki, Takako

doi:10.1155/2014/685854

Cited by 48 publications

(40 citation statements)

References 36 publications

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“…Statistical analysis of significance was calculated using one-way ANOVA followed by Tukey's post hoc test for multigroup comparisons or t test for two groups using the GraphPad Prism 6 software (GraphPad Software, Inc., San Diego, CA). regulating the inflammatory immune response (5,(17)(18)(19)(23)(24)(25). We have shown that CS reduces BMAL1 expression in mouse lungs through a SIRT1-dependent mechanism (3).…”

Section: Resultsmentioning

confidence: 99%

“…Abnormal regulation of circadian clocks in peripheral tissues is suggested to cause cell dysfunction and chronic diseases (8,30). It has been shown that the clock machinery including nuclear receptors controls inflammatory immune responses (5,17,19,(23)(24)(25)(31)(32)(33). We found that the level and expression of clock proteins (BMAL1 and PER2) and associated nuclear receptors (REV-ERBa) were reduced in PBMCs and sputum cells (mainly inflammatory cells [i.e., macrophages and neutrophils]) and in lungs from smokers and patients with COPD.…”

Section: Original Researchmentioning

confidence: 99%

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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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Section: Resultsmentioning

confidence: 99%

Section: Original Researchmentioning

confidence: 99%

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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“…Microglia rhythmically express circadian clock genes that can regulate function, including phagocytosis, inflammatory responses, and autophagy (Fonken et al, ; Ma, Li, Molusky, & Lin, ). This regulation may occur in part by mediating pro‐inflammatory chemokine expression (Lam et al, ; Sato et al, ). Microglia are highly sensitive to environmental cues and can immediately transform their morphology into distinctive phenotypes, including resting, classically activated (M1), and alternatively activated (M2) microglia (Ma, Wang, Wang, & Yang, ; Zhou et al, ).…”

Section: Introductionmentioning

confidence: 99%

“…Microglia rhythmically express circadian clock genes that can regulate function, including phagocytosis, inflammatory responses, and autophagy (Fonken et al, 2015;Ma, Li, Molusky, & Lin, 2012). This regulation may occur in part by mediating pro-inflammatory chemokine expression (Lam et al, 2013;Sato et al, 2014).…”

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confidence: 99%

Inhibition of REV‐ERBs stimulates microglial amyloid‐beta clearance and reduces amyloid plaque deposition in the 5XFAD mouse model of Alzheimer’s disease

et al. 2019

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A promising new therapeutic target for the treatment of Alzheimer's disease (AD) is the circadian system. Although patients with AD are known to have abnormal circadian rhythms and suffer sleep disturbances, the role of the molecular clock in regulating amyloid‐beta (Aβ) pathology is still poorly understood. Here, we explored how the circadian repressors REV‐ERBα and β affected Aβ clearance in mouse microglia. We discovered that, at Circadian time 4 (CT4), microglia expressed higher levels of the master clock protein BMAL1 and more rapidly phagocytosed fibrillary Aβ1‐42 (fAβ1‐42) than at CT12. BMAL1 directly drives transcription of REV‐ERB proteins, which are implicated in microglial activation. Interestingly, pharmacological inhibition of REV‐ERBs with the small molecule antagonist SR8278 or genetic knockdown of REV‐ERBs‐accelerated microglial uptake of fAβ1‐42 and increased transcription of BMAL1. SR8278 also promoted microglia polarization toward a phagocytic M2‐like phenotype with increased P2Y12 receptor expression. Finally, constitutive deletion of Rev‐erbα in the 5XFAD model of AD decreased amyloid plaque number and size and prevented plaque‐associated increases in disease‐associated microglia markers including TREM2, CD45, and Clec7a. Altogether, our work suggests a novel strategy for controlling Aβ clearance and neuroinflammation by targeting REV‐ERBs and provides new insights into the role of REV‐ERBs in AD.

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“…REV-ERBs have been shown to regulate the expression of inflammatory cytokines interleukin-6 and Ccl2 [13,14]. REV-ERBs are widely expressed and it has been demonstrated that REVERBα is expressed in macrophages found in human atherosclerotic lesions [15].…”

Section: Introductionmentioning

confidence: 99%

Suppression of atherosclerosis by synthetic REV-ERB agonist

Sitaula

Billon

Kamenecka

et al. 2015

Biochemical and Biophysical Research Communications

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The nuclear receptors for heme, REV-ERBα and REV-ERBβ, play important roles in the regulation of metabolism and inflammation. Recently it was demonstrated that reduced REV-ERBα expression in hematopoetic cells in LDL receptor null mice led to increased atherosclerosis. We sought to determine if synthetic REV-ERB agonists that we have developed might have the ability to suppress atherosclerosis in this model. A previously characterized synthetic REV-ERB agonist, SR9009, was used to determine if activation of REV-ERB activity would affect atherosclerosis in LDL receptor deficient mice. Atherosclerotic plaque size was significantly reduced (p < 0.05) in mice administered SR9009 (100 mg/kg) for seven weeks compared to control mice (n = 10 per group). SR9009 treatment of bone marrow-derived mouse macrophages (BMDM) reduced the polarization of BMDMs to proinflammatory M1 macrophage while increasing the polarization of BMDMs to anti-inflammatory M2 macrophages. Our results suggest that pharmacological targeting of REV-ERBs may be a viable therapeutic option for treatment of atherosclerosis.

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Direct and Indirect Suppression of Interleukin-6 Gene Expression in Murine Macrophages by Nuclear Orphan Receptor REV-ERBα

Cited by 48 publications

References 36 publications

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

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

Inhibition of REV‐ERBs stimulates microglial amyloid‐beta clearance and reduces amyloid plaque deposition in the 5XFAD mouse model of Alzheimer’s disease

Suppression of atherosclerosis by synthetic REV-ERB agonist

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