Circadian asthma airway responses are gated by REV-ERBα.
Durrington HJ., Krakowiak K., Meijer P., Begley N., Maidstone R., Goosey L., Gibbs JE., Blaikley JF., Gregory LG., Lloyd CM., Loudon ASI., Ray DW.
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.