A Circadian Clock Gene, Rev-erbα, Modulates the Inflammatory Function of Macrophages through the Negative Regulation of <i>Ccl2</i> Expression

Sato, Shogo; Sakurai, Takeshi; Ogasawara, Jun; Takahashi, M.; Izawa, Tetsuya; Imaizumi, Kazunori; Taniguchi, Naoyuki; Ohno, Hideki; Kizaki, Takako

doi:10.4049/jimmunol.1301982

Cited by 192 publications

(170 citation statements)

References 52 publications

(72 reference statements)

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“…6). On one hand, as the result of the absence of a phase shift in response to night shift for immune cell counts rhythms and melatonin (the current study), as well as for cortisol rhythms (56), we propose that immune cell distribution between blood and tissues is primarily regulated by the central clock, via neuronal and/or humoral regulators (e.g., cortisol) acting on adhesion molecules and chemokines (18,37,57). On the other hand, due to the presence of a phase shift in cytokine-secretion rhythms in response to night shift, we infer that the sensitivity of immune cells to stimuli (e.g., LPS or PHA in our study) or their capacity to produce cytokines in response to these stimuli is dependent on the local clocks intrinsic to these immune cells.…”

Section: Discussionmentioning

confidence: 99%

Simulated Night Shift Disrupts Circadian Rhythms of Immune Functions in Humans

Cuesta

Boudreau

Dubeau-Laramée

et al. 2016

The Journal of Immunology

100

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Recent research unveiled a circadian regulation of the immune system in rodents, yet little is known about rhythms of immune functions in humans and how they are affected by circadian disruption. In this study, we assessed rhythms of cytokine secretion by immune cells and tested their response to simulated night shifts. PBMCs were collected from nine participants kept in constant posture over 24 h under a day-oriented schedule (baseline) and after 3 d under a night-oriented schedule. Monocytes and T lymphocytes were stimulated with LPS and PHA, respectively. At baseline, a bimodal rhythmic secretion was detected for IL-1β, IL-6, and TNF-α: a night peak was primarily due to a higher responsiveness of monocytes, and a day peak was partly due to a higher proportion of monocytes. A rhythmic release was also observed for IL-2 and IFN-γ, with a nighttime peak due to a higher cell count and responsiveness of T lymphocytes. Following night shifts, with the exception of IL-2, cytokine secretion was still rhythmic but with peak levels phase advanced by 4.5–6 h, whereas the rhythm in monocyte and T lymphocyte numbers was not shifted. This suggests distinct mechanisms of regulation between responsiveness to stimuli and cell numbers of the human immune system. Under a night-oriented schedule, only cytokine release was partly shifted in response to the change in the sleep–wake cycle. This led to a desynchronization of rhythmic immune parameters, which might contribute to the increased risk for infection, autoimmune diseases, cardiovascular and metabolic disorders, and cancer reported in shift workers.

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Section: Discussionmentioning

confidence: 99%

Simulated Night Shift Disrupts Circadian Rhythms of Immune Functions in Humans

Cuesta

Boudreau

Dubeau-Laramée

et al. 2016

The Journal of Immunology

100

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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: Discussionmentioning

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%

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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“…2 Macrophages are immune effector cells that orchestrate a diverse array of functions including inflammatory response, tissue repair, immune responses, and so on. [3][4][5] Their diverse but polarized functional phenotypes, driven by micro-environmental cues, allow them to adapt readily to changing conditions within tissues. 6 In response to diverse signals derived from damaged tissues, macrophages undergo reprogramming, which leads to two different polarization states, M1 macrophages (classically activated) and M2 macrophages (alternatively activated).…”

Section: Introductionmentioning

confidence: 99%

TNF-a mediated inflammatory macrophage polarization contributes to the pathogenesis of steroid-induced osteonecrosis in mice

Feng

et al. 2015

Int J Immunopathol Pharmacol

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The phenotypic polarization of macrophages are involved in steroid-induced osteonecrosis (ON). This study tried to investigate the detrimental and beneficial roles of M1/M2 macrophages associated with TNF-a in ON. Mice ON model was induced by the injection of methylprednisolone. After that, flow cytometry technique, immunohistochemistry, immunofluorescence, ELISA, and RT-PCR methods were used to investigate the expression pattern of macrophages and the expression of inflammatory cytokines. During the progression of ON, massive chronic inflammatory cells infiltrated into the necrotic zone, represented by the infiltration of macrophages. In the early stage of ON, there was high TNF-a activity; and a large population of M1 macrophages infiltrated into the necrotic zone. On the contrary, the expression of TNF-a gradually decreased; simultaneously, a larger M2 cell population presented in the necrotic zone in the late stage of ON. The increased M2 macrophages could be beneficial for resolving inflammation and promoting tissue repair, confirmed by the histologic findings of appositional new bone formation around the necrotic bone. Thus, it showed that TNF-a-mediated alteration of M1/M2 macrophage polarization contributed to the pathogenesis of steroid-induced osteonecrosis. M1-polarized macrophages appeared to be disruptive in the early stage of ON, while M2-polarized macrophages played an important role in the late stage during the pathogenesis of ON.

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A Circadian Clock Gene, Rev-erbα, Modulates the Inflammatory Function of Macrophages through the Negative Regulation of Ccl2 Expression

Cited by 192 publications

References 52 publications

Simulated Night Shift Disrupts Circadian Rhythms of Immune Functions in Humans

Simulated Night Shift Disrupts Circadian Rhythms of Immune Functions in Humans

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

TNF-a mediated inflammatory macrophage polarization contributes to the pathogenesis of steroid-induced osteonecrosis in mice

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