The clock gene
            <i>Bmal1</i>
            inhibits macrophage motility, phagocytosis, and impairs defense against pneumonia

Kitchen, Gareth; Cunningham, Peter; Poolman, Toryn; Iqbal, Mudassar; Maidstone, Robert; Baxter, Matthew; Bagnall, James; Begley, Nicola; Saer, Ben; Hussell, Tracy; Matthews, Laura; Dockrell, David H.; Durrington, Hannah J.; Gibbs, Julie; Blaikley, John; Loudon, A. S. I.; Ray, David

doi:10.1073/pnas.1915932117

Cited by 95 publications

(96 citation statements)

References 40 publications

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“…HIV-1 establishes latent sites of infection that promote viral persistence and evasion of host immune responses and antiviral therapies 12 . HIV-1 primarily replicates in CD4 T cells and macrophages which display intrinsic rhythms of clock genes and cytokine expression 13 – 15 . Despite reports of disrupted circadian rhythms in HIV-1 infected patients 16 – 18 , there is limited evidence supporting a direct role for circadian components in regulating HIV-1 replication.…”

Section: Introductionmentioning

confidence: 99%

Pharmacological activation of the circadian component REV-ERB inhibits HIV-1 replication

Borrmann

Davies

Dickinson

et al. 2020

Sci Rep

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Human immunodeficiency virus 1 (HIV-1) is a life-threatening pathogen that still lacks a curative therapy or vaccine. Despite the reduction in AIDS-related deaths achieved by current antiretroviral therapies, drawbacks including drug resistance and the failure to eradicate infection highlight the need to identify new pathways to target the infection. Circadian rhythms are endogenous 24-h oscillations which regulate physiological processes including immune responses to infection, and there is an emerging role for the circadian components in regulating viral replication. The molecular clock consists of transcriptional/translational feedback loops that generate rhythms. In mammals, BMAL1 and CLOCK activate rhythmic transcription of genes including the nuclear receptor REV-ERBα, which represses BMAL1 and plays an essential role in sustaining a functional clock. We investigated whether REV-ERB activity regulates HIV-1 replication and found REV-ERB agonists inhibited HIV-1 promoter activity in cell lines, primary human CD4 T cells and macrophages, whilst antagonism or genetic disruption of REV-ERB increased promoter activity. The REV-ERB agonist SR9009 inhibited promoter activity of diverse HIV-subtypes and HIV-1 replication in primary T cells. This study shows a role for REV-ERB synthetic agonists to inhibit HIV-1 LTR promoter activity and viral replication, supporting a role for circadian clock components in regulating HIV-1 replication. All life forms have evolved under a rhythmically changing light/dark cycle due to the Earth's rotation. From bacteria to man, all organisms possess an internal clock that oscillates in a 24-h manner to anticipate environmental changes. The central clock and peripheral oscillators share a common molecular architecture and consist of transcriptional/translational feedback loops that regulate rhythmic gene expression 1. In mammals, BMAL1 and CLOCK dimerize and the complex can bind E-box motifs in the promoter/enhancer of various clock genes, including Per and Cry, to activate their transcription. In turn, the PER and CRY proteins repress BMAL1/CLOCK function and thereby shut down their own transcription. An additional feedback loop involves the nuclear receptors REV-ERBα and RORα. RORα competes with REV-ERBα for binding to the Bmal1 promoter ROR element (RORE) site and activates Bmal1 transcription. REV-ERBα and RORα coordinate a regulatory loop which is crucial for stabilizing the core clock machinery 2 (Fig. 1). The circadian system regulates host innate and adaptive immune responses to microbial pathogens 3-5 and host susceptibility to an infectious agent is not only dependent on the inoculum size, transmission route and length of exposure, but on the time of day when the pathogen is encountered 6. Recent clinical studies show that the time of vaccination can influence host immune responses and vaccine efficacy 7. Viruses are obligate parasites that rely on host cell synthesis machinery for their replication, survival and dissemination. The potential for circadian pathways to regulat...

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Section: Introductionmentioning

confidence: 99%

Pharmacological activation of the circadian component REV-ERB inhibits HIV-1 replication

Borrmann

Davies

Dickinson

et al. 2020

Sci Rep

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“…In addition, tissue leucocytes display circadian variations mainly due to oscillations in their rolling and adhesion to the endothelium and infiltration into tissues which predominantly occurs at the onset of the active phase ( 43 , 44 ). In parallel, immune cell functions such as cytokines production, phagocytosis of exogenous particles or response to pathogens also display daily oscillations resulting in time-of-day-dependent difference in the susceptibility to septic shock or injury ( 45 – 48 ). This temporal organization is meant to ensure an optimization of the immune response in order to maintain or rapidly and efficiently restore homeostasis after infection or injury/tissue damage.…”

Section: Circadian Control Of the Immune Systemmentioning

confidence: 99%

Circadian Control of Inflammasome Pathways: Implications for Circadian Medicine

Pourcet

Duez

2020

Front. Immunol.

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The innate immune system senses "non-self" molecules derived from pathogens (PAMPs) as well as endogenous damage-associated molecular patterns (DAMPs) and promotes sterile inflammation that is necessary for injury resolution, tissue repair/regeneration, and homeostasis. The NOD-, LRR-and pyrin domain containing protein 3 (NLRP3) is an innate immune signaling complex whose assembly and activation can be triggered by various signals ranging from microbial molecules to ATP or the abnormal accumulation of crystals, thus leading to IL-1β and IL-18 maturation and secretion. Deregulation of the NLRP3 signaling cascade is associated with numerous inflammatory and metabolic diseases including rheumatoid arthritis, gout, atherosclerosis or type 2 diabetes. Interestingly, the circadian clock controls numerous inflammatory processes while clock disruption leads to or exacerbates inflammation. Recently, the biological clock was demonstrated to control NLRP3 expression and activation, thereby controlling IL-1β and IL-18 secretion in diverse tissues and immune cells, particularly macrophages. Circadian oscillations of NLRP3 signaling is lost in models of clock disruption, contributing to the development of peritonitis, hepatitis, or colitis. Sterile inflammation is also an important driver of atherosclerosis, and targeting the production of IL-1β has proven to be a promising approach for atherosclerosis management in humans. Interestingly, the extent of injury after fulminant hepatitis or myocardial infarction is time-of-day dependent under the control of the clock, and chronotherapy represents a promising approach for the management of pathologies involving deregulation of NLRP3 signaling.

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“…Circadian clock components regulate various functions in macrophages, including cytokine secretion upon LPS challenge (70)(71)(72). About 8% of genes expressed in peritoneal macrophages are rhythmically transcribed, including essential elements in LPS/TLR4 signaling (71).…”

Section: Macrophage Responsementioning

confidence: 99%

Circadian Regulation of the Biology of Allergic Disease: Clock Disruption Can Promote Allergy

Nakao

2020

Front. Immunol.

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Allergic diseases such as allergic rhinitis, asthma, atopic dermatitis, and food allergy are characterized by epithelial barrier dysfunction and deregulated immune responses. Components of the circadian clock interact with critical elements of epithelial barrier function and immune responses, and regulate the biological processes on a 24-h cycle at steady state. This may represent an anticipatory defense response to day-night fluctuation of attack by noxious stimuli such as pathogens in the environment. This review will summarize clock control of epithelial barrier function and immune responses associated with allergic disease and offer novel insights and opportunities into how clock dysfunction impacts allergic disease. Importantly, perturbation of normal clock activity by genetic and environmental disturbances, such as chronic light cycle perturbations or irregular eating habits, deregulates epithelial barrier function and immune responses. This implies that the circadian clock is strongly linked to the fundamental biology of allergic disease, and that clock disruption can precipitate allergic disease by altering the epithelial barrier and immune functions. Given that contemporary lifestyles often involve chronic circadian disruptions such as shift work, we propose that lifestyle or therapeutic interventions that align the endogenous circadian clock with environmental cycles should be a part of the efforts to prevent or treat allergic disease in modern society.

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The clock gene Bmal1 inhibits macrophage motility, phagocytosis, and impairs defense against pneumonia

Cited by 95 publications

References 40 publications

Pharmacological activation of the circadian component REV-ERB inhibits HIV-1 replication

Pharmacological activation of the circadian component REV-ERB inhibits HIV-1 replication

Circadian Control of Inflammasome Pathways: Implications for Circadian Medicine

Circadian Regulation of the Biology of Allergic Disease: Clock Disruption Can Promote Allergy

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