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While the daily rhythm of allergic rhinitis (AR) has long been recognized, the molecular mechanism underlying this phenomenon remains enigmatic. We aimed to investigate the role of circadian clock in AR development and to clarify the mechanism by which the daily rhythm of AR is generated. AR was induced in mice with ovalbumin. Toluidine blue staining, liquid chromatography–tandem mass spectrometry analysis, real-time quantitative PCR, and immunoblotting were performed with AR and control mice. Ovalbumin-induced AR is diurnally rhythmic and associated with clock gene disruption in nasal mucosa. In particular, Rev-erbα is generally downregulated and its rhythm retained, but with a near-12-hour phase shift. Furthermore, global knockout of core clock gene Bmal1 or Rev-erbα increases the susceptibility of mice to AR and blunts AR rhythmicity. Importantly, nasal solitary chemosensory cells (SCCs) are rhythmically activated, and inhibition of the SCC pathway leads to attenuated AR and a loss of its rhythm. Moreover, rhythmic activation of SCCs is accounted for by diurnal expression of ChAT (an enzyme responsible for the synthesis of acetylcholine) and temporal generation of the neurotransmitter acetylcholine. Mechanistically, Rev-erbα trans-represses Ch at through direct binding to a specific response element, generating a diurnal oscillation in this target gene. SCCs, under the control of Rev-erbα , are a driver of AR rhythmicity; targeting SCCs should be considered as a new avenue for AR management. [ABSTRACT FROM AUTHOR]

Microgravity and sudden changes of gravitational forces exert numerous effects on tissues, organs and apparatus. Responses to these forces variably applied to cells indicate the existence of mechanotransduction pathways able to modulate transcription. Oscillation of circadian clocks similarly influences many cellular and metabolic processes. Here we hypothesized that signals derived from changes of gravitational forces applied to epidermal cells might influence their physiology in harmony with the oscillation of the molecular clock. In this study, we describe amplified oscillations of Bmal1 circadian clock gene in human keratinocytes exposed to short simulated microgravity and to rapid variation of gravitational forces. We found that exposure to microgravity enhances the amplitude of the Bmal1 feedback loop sustained by an apparently lower variability of Rev-erbα transcription, while recovery from microgravity is characterized by increased amplitude of Bmal1 expression and elongation of the oscillatory periods of Bmal1 and Rev-erbα. These data highlight the existence of integrated signaling network connecting mechanosensitive pathways to circadian gene regulation. [ABSTRACT FROM AUTHOR]

The nuclear receptor, REV-ERBα, has a key role in circadian rhythms and requires heme as its ligand. The present study determined whether the heme precursor, 5-aminolevulinic acid (ALA), affects REV-ERBα and its target genes. When exposed to ALA, the human lung diploid cell line, WI-38, exhibited activation of REV-ERBα and repression of the transcription of REV-ERBα target genes, including BMAL1 , an essential component of the circadian oscillator. Moreover, co-incubation of sodium ferrous citrate (SFC) and ALA also activated REV-ERBα and repressed the transcription of REV-ERBα target genes. These results indicate that ALA regulates human circadian rhythms via REV-ERBα. [ABSTRACT FROM AUTHOR]

The nuclear receptor, REV‐ERBα, has a key role in circadian rhythms and requires heme as its ligand. The present study determined whether the heme precursor, 5‐aminolevulinic acid (ALA), affects REV‐ERBα and its target genes. When exposed to ALA, the human lung diploid cell line, WI‐38, exhibited activation of REV‐ERBα and repression of the transcription of REV‐ERBα target genes, including BMAL1, an essential component of the circadian oscillator. Moreover, co‐incubation of sodium ferrous citrate (SFC) and ALA also activated REV‐ERBα and repressed the transcription of REV‐ERBα target genes. These results indicate that ALA regulates human circadian rhythms via REV‐ERBα. [ABSTRACT FROM AUTHOR]

Background & Aims The innate immune system responds not only to bacterial signals, but also to non-infectious danger-associated molecular patterns that activate the NLRP3 inflammasome complex after tissue injury. Immune functions vary over the course of the day, but it is not clear whether these changes affect the activity of the NLRP3 inflammasome. We investigated whether the core clock component nuclear receptor subfamily 1 group D member 1 (NR1D1, also called Rev-erbα) regulates expression, activity of the NLRP3 inflammasome, and its signaling pathway. Methods We collected naïve peritoneal macrophages and plasma, at multiple times of day, from Nr1d1 –/– mice and their Nr1d1 +/+ littermates (controls) and analyzed expression NLRP3, interleukin 1β (IL1B, in plasma), and IL18 (in plasma). We also collected bone marrow–derived primary macrophages from these mice. Levels of NR1D1 were knocked down with small hairpin RNAs in human primary macrophages. Bone marrow–derived primary macrophages from mice and human primary macrophages were incubated with lipopolysaccharide (LPS) to induce expression of NLRP3, IL1B, and IL18; cells were incubated with LPS and adenosine triphosphate to activate the NLRP3 complex. We analyzed caspase 1 activity and cytokine secretion. NR1D1 was activated in primary mouse and human macrophages by incubation with SR9009; some of the cells were also incubated with an NLRP3 inhibitor or inhibitors of caspase 1. Nr1d1 –/– mice and control mice were given intraperitoneal injections of LPS to induce peritoneal inflammation; plasma samples were isolated and levels of cytokines were measured. Nr1d1 –/– mice, control mice, and control mice given injections of SR9009 were given LPS and D-galactosamine to induce fulminant hepatitis and MCC950 to specifically inhibit NLRP3; plasma was collected to measure cytokines and a marker of liver failure (alanine aminotransferase); liver tissues were collected and analyzed by quantitative polymerase chain reaction, immunohistochemistry, and flow cytometry. Results In peritoneal macrophages, expression of NLRP3 and activation of its complex varied with time of day (circadian rhythm)—this regulation required NR1D1. Primary macrophages from Nr1d1 –/– mice and human macrophages with knockdown of NR1D1 had altered expression patterns of NLRP3, compared to macrophages that expressed NR1D1, and altered patterns of IL1B and 1L18 production. Mice with disruption of Nr1d1 developed more-severe acute peritoneal inflammation and fulminant hepatitis than control mice. Incubation of macrophage with the NR1D1 activator SR9009 reduced expression of NLRP3 and secretion of cytokines. Mice given SR9009 developed less-severe liver failure and had longer survival times than mice given saline (control). Conclusions In studies of Nr1d1 –/– mice and human macrophages with pharmacologic activation of NR1D1, we found NR1D1 to regulate the timing of NLRP3 expression and production of inflammatory cytokines by macrophages. Activation of NR1D1 reduced the severity of peritoneal inflammation and fulminant hepatitis in mice. [ABSTRACT FROM AUTHOR]