Circadian asthma airway responses are gated by REV-ERBα.
内科学
气道
作者
Hannah J. Durrington,Karolina Krakowiak,Peter Meijer,Nicola Begley,Robert Maidstone,Laurence C. Goosey,Julie E. Gibbs,John Blaikley,Lisa G. Gregory,Clare M. Lloyd,Andrew S. I. Loudon,David W. Ray
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.