An epithelial circadian clock controls pulmonary inflammation and glucocorticoid action

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

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • ARNTL Transcription Factors / genetics
  • ARNTL Transcription Factors / immunology*
  • Animals
  • Cells, Cultured
  • Chemokine CXCL5 / biosynthesis
  • Chemokine CXCL5 / immunology*
  • Circadian Clocks / immunology*
  • Circadian Rhythm / physiology
  • Dexamethasone / pharmacology
  • Epithelial Cells / immunology
  • Glucocorticoids / pharmacology*
  • Humans
  • Lipopolysaccharides / immunology
  • Lung / immunology
  • Lung / microbiology
  • Lung / pathology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Neutrophil Infiltration / immunology
  • Neutrophils / immunology
  • Period Circadian Proteins / immunology
  • Pneumonia, Pneumococcal / genetics
  • Pneumonia, Pneumococcal / immunology*
  • Receptors, Glucocorticoid / immunology
  • Streptococcus pneumoniae*
  • Uteroglobin / genetics

Substances

  • ARNTL Transcription Factors
  • Arntl protein, mouse
  • Chemokine CXCL5
  • Cxcl5 protein, mouse
  • Glucocorticoids
  • Lipopolysaccharides
  • Period Circadian Proteins
  • Receptors, Glucocorticoid
  • Scgb1a1 protein, mouse
  • Dexamethasone
  • Uteroglobin