Dataset Information

Circadian asthma airway responses are gated by REV-ERBα.

ABSTRACT:

Background

The circadian clock powerfully regulates inflammation and the clock protein REV-ERBα is known to play a key role as a repressor of the inflammatory response. Asthma is an inflammatory disease of the airways with a strong time of day rhythm. Airway hyper-responsiveness (AHR) is a dominant feature of asthma; however, it is not known if this is under clock control.

Objectives

To determine if allergy-mediated AHR is gated by the clock protein REV-ERBα.

Methods

After exposure to the intra-nasal house dust mite (HDM) allergen challenge model at either dawn or dusk, AHR to methacholine was measured invasively in mice.

Main results

Wild-type (WT) mice show markedly different time of day AHR responses (maximal at dusk/start of the active phase), both in vivo and ex vivo, in precision cut lung slices. Time of day effects on AHR were abolished in mice lacking the clock gene Rev-erbα, indicating that such effects on asthma response are likely to be mediated via the circadian clock. We suggest that muscarinic receptors one (Chrm 1) and three (Chrm 3) may play a role in this pathway.

Conclusions

We identify a novel circuit regulating a core process in asthma, potentially involving circadian control of muscarinic receptor expression, in a REV-ERBα dependent fashion.

Clinical implication

These insights suggest the importance of considering the timing of drug administration in clinic trials and in clinical practice (chronotherapy).

SUBMITTER: Durrington HJ

PROVIDER: S-EPMC7613655 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature

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Publications

Circadian asthma airway responses are gated by REV-ERBα.

Durrington Hannah J HJ Krakowiak Karolina K Meijer Peter P Begley Nicola N Maidstone Robert R Goosey Laurence L Gibbs Julie E JE Blaikley John F JF Gregory Lisa G LG Lloyd Clare M CM Loudon Andrew S I ASI Ray David W DW

The European respiratory journal 20201217 6

<h4>Background</h4>The circadian clock powerfully regulates inflammation and the clock protein REV-ERBα is known to play a key role as a repressor of the inflammatory response. Asthma is an inflammatory disease of the airways with a strong time of day rhythm. Airway hyper-responsiveness (AHR) is a dominant feature of asthma; however, it is not known if this is under clock control.<h4>Objectives</h4>To determine if allergy-mediated AHR is gated by the clock protein REV-ERBα.<h4>Methods</h4>After ...[more]

PMID: 32586876

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Project description:Circadian dysfunction is a common attribute of many neurodegenerative diseases, most of which are associated with neuroinflammation. Circadian rhythm dysfunction has been associated with inflammation in the periphery, but the role of the core clock in neuroinflammation remains poorly understood. Here we demonstrate that Rev-erbα, a nuclear receptor and circadian clock component, is a mediator of microglial activation and neuroinflammation. We observed time-of-day oscillation in microglial immunoreactivity in the hippocampus, which was disrupted in Rev-erbα-/- mice. Rev-erbα deletion caused spontaneous microglial activation in the hippocampus and increased expression of proinflammatory transcripts, as well as secondary astrogliosis. Transcriptomic analysis of hippocampus from Rev-erbα-/- mice revealed a predominant inflammatory phenotype and suggested dysregulated NF-κB signaling. Primary Rev-erbα-/- microglia exhibited proinflammatory phenotypes and increased basal NF-κB activation. Chromatin immunoprecipitation revealed that Rev-erbα physically interacts with the promoter regions of several NF-κB-related genes in primary microglia. Loss of Rev-erbα in primary astrocytes had no effect on basal activation but did potentiate the inflammatory response to lipopolysaccharide (LPS). In vivo, Rev-erbα-/- mice exhibited enhanced hippocampal neuroinflammatory responses to peripheral LPS injection, while pharmacologic activation of Rev-erbs with the small molecule agonist SR9009 suppressed LPS-induced hippocampal neuroinflammation. Rev-erbα deletion influenced neuronal health, as conditioned media from Rev-erbα-deficient primary glial cultures exacerbated oxidative damage in cultured neurons. Rev-erbα-/- mice also exhibited significantly altered cortical resting-state functional connectivity, similar to that observed in neurodegenerative models. Our results reveal Rev-erbα as a pharmacologically accessible link between the circadian clock and neuroinflammation.

Dataset Information

Circadian asthma airway responses are gated by REV-ERBα.

Background

Objectives

Methods

Main results

Conclusions

Clinical implication

Publications

Circadian asthma airway responses are gated by REV-ERBα.

Similar Datasets

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