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Nat Med. 2014 Aug;20(8):919-26. doi: 10.1038/nm.3599. Epub 2014 Jul 27.

An epithelial circadian clock controls pulmonary inflammation and glucocorticoid action.

Author information

1
Faculty of Medical and Human Sciences, University of Manchester, Manchester Academic Health Sciences Centre, Manchester, UK.
2
Faculty of Life Sciences, University of Manchester, Manchester, UK.
3
Division of Neonatology, Children's Hospital of Philadelphia, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
4
Manchester Collaborative Centre for Inflammation Research, Core Technology Facility, University of Manchester, Manchester, UK.
5
1] Faculty of Medical and Human Sciences, University of Manchester, Manchester Academic Health Sciences Centre, Manchester, UK. [2] Respiratory Therapy Area, GlaxoSmithKline, Stevenage, UK.
6
Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, Texas, USA.

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.

PMID:
25064128
PMCID:
PMC4268501
DOI:
10.1038/nm.3599
[Indexed for MEDLINE]
Free PMC Article

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