Circadian asthma airway responses are gated by REV-ERBα

Hannah J. Durrington, Karolina Krakowiak, Peter Meijer, Nicola Begley, Robert Maidstone, Laurence Goosey, Julie E. Gibbs, John F. Blaikley, Lisa G. Gregory, Clare M. Lloyd, Andrew S. I. Loudon, D. W. Ray

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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).
Original languageUndefined
Article number1902407
JournalEuropean Respiratory Journal
Volume56
DOIs
Publication statusPublished - 25 Jun 2020

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