Durrington Hannah J, Krakowiak Karolina, Meijer Peter, Begley Nicola, Maidstone Robert, Goosey Laurence, Gibbs Julie E, Blaikley John F, Gregory Lisa G, Lloyd Clare M, Loudon Andrew S I, Ray David W
Division of Infection, Immunity and Respiratory Medicine, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK
Wythenshawe Hospital, University Hospital of South Manchester, Manchester University NHS Foundation Trust (MFT), Manchester, UK.
Eur Respir J. 2020 Dec 17;56(6). doi: 10.1183/13993003.02407-2019. Print 2020 Dec.
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.
To determine if allergy-mediated AHR is gated by the clock protein REV-ERBα.
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.
Wild-type (WT) mice show markedly different time of day AHR responses (maximal at dusk/start of the active phase), both and , in precision cut lung slices. Time of day effects on AHR were abolished in mice lacking the clock gene α, indicating that such effects on asthma response are likely to be mediated the circadian clock. We suggest that muscarinic receptors one () and three () may play a role in this pathway.
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.
These insights suggest the importance of considering the timing of drug administration in clinic trials and in clinical practice (chronotherapy).
昼夜节律钟强力调节炎症反应，已知时钟蛋白REV-ERBα作为炎症反应的抑制因子发挥关键作用。哮喘是一种气道炎症性疾病，具有强烈的昼夜节律。气道高反应性（AHR）是哮喘的主要特征；然而，尚不清楚其是否受昼夜节律钟的控制。
确定过敏介导的AHR是否受时钟蛋白REV-ERBα的调控。
在黎明或黄昏时，将小鼠暴露于鼻内屋尘螨（HDM）过敏原激发模型后，以侵入性方式测量小鼠对乙酰甲胆碱的AHR。
野生型（WT）小鼠在精密切割肺切片中显示出明显不同的昼夜AHR反应时间（在黄昏/活动期开始时最大）。在缺乏时钟基因α的小鼠中，昼夜对AHR的影响消失，表明对哮喘反应的此类影响可能由昼夜节律钟介导。我们认为毒蕈碱受体M1和M3可能在此途径中起作用。
我们确定了一种调节哮喘核心过程的新途径，可能以REV-ERBα依赖的方式涉及毒蕈碱受体表达的昼夜控制。
这些见解表明在临床试验和临床实践（时间疗法）中考虑给药时间的重要性。
