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Cited by 455

The DOI matches its Crossref record; 51 of the 51 references it cites were found in a registry or an index.

An epithelial circadian clock controls pulmonary inflammation and glucocorticoid action

Open access
Gibbs, Julie, Ince, Louise, Matthews, Laura, Mei, Junjie, Bell, Thomas, Yang, Nan, Saer, Ben, Begley, Nicola, Poolman, Toryn, Pariollaud, Marie, Farrow, Stuart, DeMayo, Francesco, Hussell, Tracy, Worthen, G Scott, Ray, David, Loudon, Andrew·2014·Nature Medicine
DOI 10.1038/nm.3599
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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.

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Metadata

Authors
Gibbs, J., Ince, L., Matthews, L., Mei, J., Bell, T., Yang, N., Saer, B., Begley, N., Poolman, T., Pariollaud, M., Farrow, S., DeMayo, F., Hussell, T., Worthen, G. S., Ray, D., & Loudon, A.
Venue
Nature Medicine
Publisher
Springer Science and Business Media LLC
Published
2014-07-27
Volume
20
Issue
8
Pages
919-926
ISSN
  • 1078-8956 (ISSN-L)
  • 1546-170X
DOI
10.1038/nm.3599
OpenAlex
W2110923983
Cited by
455
References
51
FWCI
13.06
Type
journal article
Language
en
Open access
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