Hannah J Durrington1,2, Karolina Krakowiak3, Peter Meijer4, Nicola Begley4, Robert Maidstone5, Laurence Goosey4, Julie E Gibbs4, John F Blaikley3,2, Lisa G Gregory6, Clare M Lloyd6, Andrew S I Loudon4, David W Ray4,7,8. 1. Division of Infection, Immunity and Respiratory Medicine, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK Hannah.durrington@manchester.ac.uk. 2. Wythenshawe Hospital, University Hospital of South Manchester, Manchester University NHS Foundation Trust (MFT), Manchester, UK. 3. Division of Infection, Immunity and Respiratory Medicine, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK. 4. Division of Diabetes, Endocrinology and Gastroenterology, School of Medical Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK. 5. Division of Informatics, Imaging and Data Sciences, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK. 6. National Heart and Lung Institute, Imperial College, London, UK. 7. NIHR Oxford Biomedical Research Centre, John Radcliffe Hospital, Oxford, UK. 8. Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, UK.
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).
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).
Authors: Julie E Gibbs; John Blaikley; Stephen Beesley; Laura Matthews; Karen D Simpson; Susan H Boyce; Stuart N Farrow; Kathryn J Else; Dave Singh; David W Ray; Andrew S I Loudon Journal: Proc Natl Acad Sci U S A Date: 2011-12-19 Impact factor: 11.205
Authors: Julie Gibbs; Louise Ince; Laura Matthews; Junjie Mei; Thomas Bell; Nan Yang; Ben Saer; Nicola Begley; Toryn Poolman; Marie Pariollaud; Stuart Farrow; Francesco DeMayo; Tracy Hussell; G Scott Worthen; David Ray; Andrew Loudon Journal: Nat Med Date: 2014-07-27 Impact factor: 53.440
Authors: Zhenguang Zhang; Louise Hunter; Gang Wu; Robert Maidstone; Yasutaka Mizoro; Ryan Vonslow; Mark Fife; Thomas Hopwood; Nicola Begley; Ben Saer; Ping Wang; Peter Cunningham; Matthew Baxter; Hannah Durrington; John F Blaikley; Tracy Hussell; Magnus Rattray; John B Hogenesch; Julie Gibbs; David W Ray; Andrew S I Loudon Journal: FASEB J Date: 2019-02-22 Impact factor: 5.834
Authors: Jeffrey A Haspel; Sukrutha Chettimada; Rahamthulla S Shaik; Jen-Hwa Chu; Benjamin A Raby; Manuela Cernadas; Vincent Carey; Vanessa Process; G Matthew Hunninghake; Emeka Ifedigbo; James A Lederer; Joshua Englert; Ashley Pelton; Anna Coronata; Laura E Fredenburgh; Augustine M K Choi Journal: Nat Commun Date: 2014-09-11 Impact factor: 14.919
Authors: Xinhui Wu; I Sophie T Bos; Thomas M Conlon; Meshal Ansari; Vicky Verschut; Luke van der Koog; Lars A Verkleij; Angela D'Ambrosi; Aleksey Matveyenko; Herbert B Schiller; Melanie Königshoff; Martina Schmidt; Loes E M Kistemaker; Ali Önder Yildirim; Reinoud Gosens Journal: Sci Adv Date: 2022-03-23 Impact factor: 14.136