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).
Abstract
REV-ERBα gates airway hyper-responsiveness by time of day. Future asthma therapies should aim to dose anti-muscarinic agents at the most efficacious time of day (chronotherapy) and modulate the molecular clock https://bit.ly/37qY4sC
Footnotes
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Author contributions: H.J. Durrington conceived of the study, secured the funding, ran the study, analysed the results and prepared the manuscript. K. Krakowiak performed Bioplex, PCR, histology, cell counts and lung slice experiments. P. Meijer performed lung slice experiments. N. Begley and L. Goosey performed FlexiVent measurements and collected samples. L.G. Gregory and C.M. Lloyd advised on the house dust mite model and FlexiVent measurements, and helped to prepare the manuscript. R. Maidstone ran statistical analysis and advised on the statistics used and prepared the manuscript. A.S.I. Loudon, J.E. Gibbs and J.F. Blaikley prepared the manuscript. J.F. Blaikley also advised on lung slice experiments. D.W. Ray conceived the study, analysed the results and prepared the manuscript.
Conflict of interest: K. Krakowiak has nothing to disclose.
Conflict of interest: P. Meijer has nothing to disclose.
Conflict of interest: N. Begley has nothing to disclose.
Conflict of interest: R. Maidstone has nothing to disclose.
Conflict of interest: L. Goosey has nothing to disclose.
Conflict of interest: J.E. Gibbs has nothing to disclose.
Conflict of interest: J.F. Blaikley has nothing to disclose.
Conflict of interest: L.G. Gregory has nothing to disclose.
Conflict of interest: C.M. Lloyd has nothing to disclose.
Conflict of interest: A.S.I. Loudon has nothing to disclose.
Conflict of interest: D.W. Ray has nothing to disclose.
Conflict of interest: H.J. Durrington has nothing to disclose.
Support statement: H.J. Durrington is supported by an Asthma UK Senior Clinical Academic Development Award (AUK-SCAD-2013–229), the JP Moulton Charitable Foundation, a North West Lung Centre charity project grant (R 121399) and the University of Manchester's Dean's Prize for Clinicians. K. Krakowiak is supported by the JP Moulton Charitable Foundation. P. Meijer is supported by Medical Research Council Doctoral Training Partnership funding (AA07 P117413). R. Maidstone is funded by a Wellcome Trust grant (107849/Z/15/Z) and a Medical Research Council grant (MR/P023576/1). J.E. Gibbs is a Career Development Fellow versus Arthritis (20629) and holds a Medical Research Council grant (MR/S002715/1). C.M. Lloyd is a Wellcome Senior Fellow in Basic Biomedical Sciences (107059/Z/15/Z). A.S.I. Loudon is a Wellcome Investigator (Wellcome Trust 107849/Z/15/Z). D.W. Ray is a Wellcome Investigator (Wellcome Trust 107849/Z/15/Z) and holds a Medical Research Council grant (MR/P023576/1). J.F. Blaikley is funded by a Medical Research Council grant (MR/L006499/1). Funding information for this article has been deposited with the Crossref Funder Registry.
- Received December 16, 2019.
- Accepted June 6, 2020.
- Copyright ©ERS 2020
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