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Circadian asthma airway responses are gated by REV-ERBα


Abstract

Background Asthma is an inflammatory disease of the airway showing a strong time of day rhythm. Airway hyperresponsiveness is a dominant feature of asthma, but it is not known if this is under clock control. The circadian clock powerfully regulates inflammation. The clock protein REV-ERBα is known to play a key role as a repressor of the inflammatory response.

Objectives To determine if allergy mediated airway hyperresponsiveness is gated by the clock protein, REV-ERBα.

Methods After exposure to the intra-nasal house dust mite allergen challenge model at either dawn or dusk, airway hyper-responsiveness to methacholine was measured invasively in mice.

Main Results Wild-type mice showed marked time-of-day differential responses of airway hyper-responsiveness (maximal at dusk, start of the active phase), both in vivo and ex vivo in precision cut lung slices. Hyper-responsive time of day effects were abolished in mice lacking the clock gene Rev-erbα, indicating that time-of-day effects on asthma responses are likely mediated via the circadian clock. We suggest that muscarinic receptors 1 and 3 (Chrm 1, 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 timing of drug administration in clinic trials, and in clinical practice; chronotherapy.

Footnotes

This manuscript has recently been accepted for publication in the European Respiratory Journal. It is published here in its accepted form prior to copyediting and typesetting by our production team. After these production processes are complete and the authors have approved the resulting proofs, the article will move to the latest issue of the ERJ online. Please open or download the PDF to view this article.

Conflict of interest: Dr. Durrington has nothing to disclose.

Conflict of interest: Miss Karolina Krakowiak has nothing to disclose.

Conflict of interest: Dr. Meijer has nothing to disclose.

Conflict of interest: Dr. Begley has nothing to disclose.

Conflict of interest: Dr. Maidstone has nothing to disclose.

Conflict of interest: Dr. Goosey has nothing to disclose.

Conflict of interest: Dr. Gibbs has nothing to disclose.

Conflict of interest: Dr. Blaikley has nothing to disclose.

Conflict of interest: Dr. Gregory has nothing to disclose.

Conflict of interest: Dr. Lloyd has nothing to disclose.

Conflict of interest: Dr. Loudon has nothing to disclose.

Conflict of interest: Dr. Ray has nothing to disclose.

  • Received December 16, 2019.
  • Accepted June 6, 2020.

sumber : https://erj.ersjournals.com/content/early/2020/06/11/13993003.02407-2019?papetoc=&utm_source=TrendMD&utm_medium=cpc&utm_campaign=European_Respiratory_Journal_TrendMD_0

 
 

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