Circadian rhythms in adaptive immunity

Downton, Polly; Early, James O.; Gibbs, Julie

doi:10.1111/imm.13167

“…Circadian rhythm is an inherent survival instinct of organisms that enables them to predict and prepare for predictable environmental changes caused by the earth's daily rotation. The circadian rhythm disturbance caused by insomnia and shift work can lead to many sub-health conditions and diseases, such as obesity, diabetes, osteoarthritis, cardiovascular disease, and so on (Downton et al, 2019;Rijo-Ferreira and Takahashi, 2019;Albrecht, 2020). The circadian clock consists of central clock pacemaker and peripheral clock receptor.…”

Section: Introductionmentioning

confidence: 99%

Circadian Rhythm Protein Bmal1 Modulates Cartilage Gene Expression in Temporomandibular Joint Osteoarthritis via the MAPK/ERK Pathway

Chen

¹

,

Zhao

²

,

Ma

³

et al. 2020

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The purpose of this study was to elucidate the role of the circadian gene Bmal1 in human cartilage and its crosstalk with the MAPK/ERK signaling pathway in temporomandibular joint osteoarthritis (TMJ-OA). We verified the periodical variation of the circadian gene Bmal1 and then established a modified multiple platform method (MMPM) to induce circadian rhythm disturbance leading to TMJ-OA. IL-6, pERK , and Bmal1 mRNA and protein expression levels were assessed by real-time RT-PCR and immunohistochemistry. Chondrocytes were treated with an ERK inhibitor (U0126), siRNA and plasmid targeting Bmal1 under IL-6 simulation; then, the cells were subjected to Western blotting to analyze the relationship between Bmal1 and the MAPK/ERK pathway. We found that sleep rhythm disturbance can downregulate the circadian gene BMAL-1 and improve phosphorylated ERK (p-ERK) and IL-6 levels. Furthermore, Bmal1 siRNA transfection was sufficient to improve the pERK level and aggravate OA-like gene expression changes under IL-6 stimulation. Bmal1 overexpression relieved the alterations induced by IL-6, which was consistent with the effect of U0126 (an ERK inhibitor). However, we also found that BMAL1 upregulation can decrease ERK phosphorylation, whereas ERK downregulation did not change BMAL1 expression. Collectively, this study provides new insight into the regulatory mechanism that links chondrocyte BMAL1 to cartilage maintenance and repair in TMJ-OA via the MAPK/ERK pathway and suggests that circadian rhythm disruption is a risk factor for TMJ-OA.

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“…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 .…”

Section: Introductionmentioning

confidence: 99%

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

Borrmann

¹

,

Davies

²

,

Dickinson

³

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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“…Of note, these compounds showed no detectable cytotoxicity in any of the cell types used (SFig. [3][4][5].…”

Section: Resultsmentioning

confidence: 91%

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

Borrmann

¹

,

Davies

²

,

Dickinson

³

et al. 2020

Preprint

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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-hour oscillations which regulate physiological processes including immune responses to infection, and there is an emerging role for the circadian components participating viral replication. The molecular clock consists of transcriptional/translational feedback loops that generate rhythms. In mammals, CLOCK and BMAL1 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. Furthermore, the REV-ERB agonist SR9009 inhibited promoter activity of different HIV-subtypes and HIV-1 replication in primary T cells. This study shows a role for REV-ERB synthetic ligands to inhibit HIV-1 LTR promoter activity and viral replication, supporting a role for circadian clock transcription factors in regulating HIV-1 replication.

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Circadian rhythms in adaptive immunity

Cited by 53 publications

References 69 publications

Circadian Rhythm Protein Bmal1 Modulates Cartilage Gene Expression in Temporomandibular Joint Osteoarthritis via the MAPK/ERK Pathway

Circadian Rhythm Protein Bmal1 Modulates Cartilage Gene Expression in Temporomandibular Joint Osteoarthritis via the MAPK/ERK Pathway

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

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

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