title: An epithelial circadian clock controls pulmonary inflammation and glucocorticoid action.
abstract: The circadian system is an important regulator of immune function. Human inflammatory lung diseases frequently show time-of-day variation in symptom severity and lung function, but the mechanisms and cell types underlying these effects remain unclear. We show that pulmonary antibacterial responses are modulated by a circadian clock within epithelial club (Clara) cells. These drive circadian neutrophil recruitment to the lung via the chemokine CXCL5. Genetic ablation of the clock gene Bmal1 (also called Arntl or MOP3) in bronchiolar cells disrupts rhythmic Cxcl5 expression, resulting in exaggerated inflammatory responses to lipopolysaccharide and an impaired host response to Streptococcus pneumoniae infection. Adrenalectomy blocks rhythmic inflammatory responses and the circadian regulation of CXCL5, suggesting a key role for the adrenal axis in driving CXCL5 expression and pulmonary neutrophil recruitment. Glucocorticoid receptor occupancy at the Cxcl5 locus shows circadian oscillations, but this is disrupted in mice with bronchiole-specific ablation of Bmal1, leading to enhanced CXCL5 expression despite normal corticosteroid secretion. The therapeutic effects of the synthetic glucocorticoid dexamethasone depend on intact clock function in the airway. We now define a regulatory mechanism that links the circadian clock and glucocorticoid hormones to control both time-of-day variation and the magnitude of pulmonary inflammation and responses to bacterial infection.
authors: Faculty of Medical and Human Sciences, University of Manchester, Manchester Academic Health Sciences Centre, Manchester, UK.
authors: Julie
authors: J
authors: Gibbs
authors: Faculty of Life Sciences, University of Manchester, Manchester, UK.
authors: Louise
authors: L
authors: Ince
authors: Faculty of Medical and Human Sciences, University of Manchester, Manchester Academic Health Sciences Centre, Manchester, UK.
authors: Laura
authors: L
authors: Matthews
authors: Division of Neonatology, Children's Hospital of Philadelphia, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors: Junjie
authors: J
authors: Mei
authors: Manchester Collaborative Centre for Inflammation Research, Core Technology Facility, University of Manchester, Manchester, UK.
authors: Thomas
authors: T
authors: Bell
authors: Faculty of Medical and Human Sciences, University of Manchester, Manchester Academic Health Sciences Centre, Manchester, UK.
authors: Nan
authors: N
authors: Yang
authors: Faculty of Life Sciences, University of Manchester, Manchester, UK.
authors: Ben
authors: B
authors: Saer
authors: Faculty of Life Sciences, University of Manchester, Manchester, UK.
authors: Nicola
authors: N
authors: Begley
authors: Faculty of Medical and Human Sciences, University of Manchester, Manchester Academic Health Sciences Centre, Manchester, UK.
authors: Toryn
authors: T
authors: Poolman
authors: Faculty of Medical and Human Sciences, University of Manchester, Manchester Academic Health Sciences Centre, Manchester, UK.
authors: Marie
authors: M
authors: Pariollaud
authors: 1] Faculty of Medical and Human Sciences, University of Manchester, Manchester Academic Health Sciences Centre, Manchester, UK. [2] Respiratory Therapy Area, GlaxoSmithKline, Stevenage, UK.
authors: Stuart
authors: S
authors: Farrow
authors: Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, Texas, USA.
authors: Francesco
authors: F
authors: DeMayo
authors: Manchester Collaborative Centre for Inflammation Research, Core Technology Facility, University of Manchester, Manchester, UK.
authors: Tracy
authors: T
authors: Hussell
authors: Division of Neonatology, Children's Hospital of Philadelphia, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors: G Scott
authors: GS
authors: Worthen
authors: Faculty of Medical and Human Sciences, University of Manchester, Manchester Academic Health Sciences Centre, Manchester, UK.
authors: David
authors: D
authors: Ray
authors: Faculty of Life Sciences, University of Manchester, Manchester, UK.
authors: Andrew
authors: A
authors: Loudon
mesh_terms: D056930:ARNTL Transcription Factors / Q000235:genetics / Q000276:immunology*; D000818:Animals; D002478:Cells, Cultured; D054365:Chemokine CXCL5 / Q000096:biosynthesis / Q000276:immunology*; D057906:Circadian Clocks / Q000276:immunology*; D002940:Circadian Rhythm / Q000502:physiology; D003907:Dexamethasone / Q000494:pharmacology; D004847:Epithelial Cells / Q000276:immunology; D005938:Glucocorticoids / Q000494:pharmacology*; D006801:Humans; D008070:Lipopolysaccharides / Q000276:immunology; D008168:Lung / Q000276:immunology / Q000382:microbiology / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020556:Neutrophil Infiltration / Q000276:immunology; D009504:Neutrophils / Q000276:immunology; D056950:Period Circadian Proteins / Q000276:immunology; D011018:Pneumonia, Pneumococcal / Q000235:genetics / Q000276:immunology*; D011965:Receptors, Glucocorticoid / Q000276:immunology; D013296:Streptococcus pneumoniae; D014598:Uteroglobin / Q000235:genetics
chemical_list: D056930:ARNTL Transcription Factors; C538961:Bmal1 protein, mouse; D054365:Chemokine CXCL5; C094739:Cxcl5 protein, mouse; D005938:Glucocorticoids; D008070:Lipopolysaccharides; D056950:Period Circadian Proteins; D011965:Receptors, Glucocorticoid; C556390:Scgb1a1 protein, mouse; D003907:Dexamethasone; D014598:Uteroglobin