RESEARCH HIGHLIGHTS Nature Reviews Immunology | AOP, published online 18 August 2014; doi:10.1038/nri3732
MUCOSAL IMMUNOLOGY
Killing time in the lungs Further experiments indicated that the Cxcl5 promoter does not have intrinsic circadian rhythmicity. Instead, Cxcl5 promoter activity was found to be strongly repressed in a rhythmic manner by glucocorticoid receptor (GR) occupancy; in Ccsp–Bmal1–/– mice, GR recruitment to Cxcl5 was reduced and no longer rhythmic. Finally, the authors showed that clock-controlled GR recruitment in epithelial club cells is necessary for the anti-inflammatory activity of steroids in the inflamed lungs. Control mice that were treated with dexamethasone showed decreased neutrophil recruitment in response to pulmonary LPS challenge, but this suppressive effect of dexamethasone was not observed in Ccsp–Bmal1–/– mice. These findings offer a possible explanation for why disease symptoms may show time-of-day variation in patients with inflammatory lung conditions. Furthermore, they suggest that the therapeutic efficacy of glucocorticoids in these patients is likely to depend on intact clock function in airway epithelial cells. Yvonne Bordon ORIGINAL RESEARCH PAPER Gibbs, J. et al. An epithelial circadian clock controls pulmonary inflammation and glucocorticoid action. Nature Med. http://dx.doi.org/10.1038/nm.3599 (2014)
S.Bradbrook/NPG
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antibacterial immune responses in the lungs are under circadian control
core clock gene Bmal1 (also known as Arntl) had similar clock-regulated responses to pulmonary LPS challenge as control mice. By contrast, Ccsp–Bmal1–/– mice (which specifically lack Bmal1 in the epithelial club cells that line the bronchioles) showed disruption of circadian rhythms in the lungs. In response to LPS challenge, Ccsp–Bmal1–/– mice had a marked increase in neutrophilia and a loss of circadian control of neutrophil recruitment. Notably, the increased neutrophil recruitment seen in the Ccsp–Bmal1–/– mice did not correlate with a stronger anti bacterial response following infection with S. pneumoniae. Closer analysis revealed that the loss of circadian control of neutrophil recruitment was owing to disrupted expression of the neutrophil chemoattractant CXCL5, with Ccsp–Bmal1–/– mice secreting increased amounts of this cytokine in response to pulmonary LPS challenge. Indeed, the authors found that expression of Cxcl5 by bronchiolar epithelial cells is rhythmic, suggesting that this chemokine is important for circadian control of inflammatory responses in the lungs.
II III IV
Inflammatory lung diseases often show time-of-day variation in their severity, but the reasons for this have not been clear. Gibbs et al. now report that antibacterial immune responses in the lungs are under circadian control. They show that pulmonary epithelial cells secrete CXC-chemokine ligand 5 (CXCL5) in a clock-dependent manner, leading to rhythmic recruitment of neutrophils to the lungs. To examine how the circadian clock regulates pulmonary immune responses, the authors challenged mice with aerosolized lipopoly saccharide (LPS) at different circadian time-points. They found that LPSinduced neutrophil recruitment and cytokine production in the lungs are regulated by the circadian clock. In keeping with this, immunity to bacterial infection in the lungs showed a circadian rhythm; mice infected with Streptococcus pneumoniae had greater neutrophil recruitment and reduced bacterial burdens in the lungs when they were infected at dawn compared with when they were infected at dusk. The authors found that mice in which macrophages and neutrophils were deficient for the
VI VII NATURE REVIEWS | IMMUNOLOGY
VOLUME 14 | SEPTEMBER 2014 © 2014 Macmillan Publishers Limited. All rights reserved
MUCOSAL IMMUNOLOGY
Killing time in the lungs Further experiments indicated that the Cxcl5 promoter does not have intrinsic circadian rhythmicity. Instead, Cxcl5 promoter activity was found to be strongly repressed in a rhythmic manner by glucocorticoid receptor (GR) occupancy; in Ccsp–Bmal1–/– mice, GR recruitment to Cxcl5 was reduced and no longer rhythmic. Finally, the authors showed that clock-controlled GR recruitment in epithelial club cells is necessary for the anti-inflammatory activity of steroids in the inflamed lungs. Control mice that were treated with dexamethasone showed decreased neutrophil recruitment in response to pulmonary LPS challenge, but this suppressive effect of dexamethasone was not observed in Ccsp–Bmal1–/– mice. These findings offer a possible explanation for why disease symptoms may show time-of-day variation in patients with inflammatory lung conditions. Furthermore, they suggest that the therapeutic efficacy of glucocorticoids in these patients is likely to depend on intact clock function in airway epithelial cells. Yvonne Bordon ORIGINAL RESEARCH PAPER Gibbs, J. et al. An epithelial circadian clock controls pulmonary inflammation and glucocorticoid action. Nature Med. http://dx.doi.org/10.1038/nm.3599 (2014)
S.Bradbrook/NPG
IX
V
X XI
XII I
VIII
antibacterial immune responses in the lungs are under circadian control
core clock gene Bmal1 (also known as Arntl) had similar clock-regulated responses to pulmonary LPS challenge as control mice. By contrast, Ccsp–Bmal1–/– mice (which specifically lack Bmal1 in the epithelial club cells that line the bronchioles) showed disruption of circadian rhythms in the lungs. In response to LPS challenge, Ccsp–Bmal1–/– mice had a marked increase in neutrophilia and a loss of circadian control of neutrophil recruitment. Notably, the increased neutrophil recruitment seen in the Ccsp–Bmal1–/– mice did not correlate with a stronger anti bacterial response following infection with S. pneumoniae. Closer analysis revealed that the loss of circadian control of neutrophil recruitment was owing to disrupted expression of the neutrophil chemoattractant CXCL5, with Ccsp–Bmal1–/– mice secreting increased amounts of this cytokine in response to pulmonary LPS challenge. Indeed, the authors found that expression of Cxcl5 by bronchiolar epithelial cells is rhythmic, suggesting that this chemokine is important for circadian control of inflammatory responses in the lungs.
II III IV
Inflammatory lung diseases often show time-of-day variation in their severity, but the reasons for this have not been clear. Gibbs et al. now report that antibacterial immune responses in the lungs are under circadian control. They show that pulmonary epithelial cells secrete CXC-chemokine ligand 5 (CXCL5) in a clock-dependent manner, leading to rhythmic recruitment of neutrophils to the lungs. To examine how the circadian clock regulates pulmonary immune responses, the authors challenged mice with aerosolized lipopoly saccharide (LPS) at different circadian time-points. They found that LPSinduced neutrophil recruitment and cytokine production in the lungs are regulated by the circadian clock. In keeping with this, immunity to bacterial infection in the lungs showed a circadian rhythm; mice infected with Streptococcus pneumoniae had greater neutrophil recruitment and reduced bacterial burdens in the lungs when they were infected at dawn compared with when they were infected at dusk. The authors found that mice in which macrophages and neutrophils were deficient for the
VI VII NATURE REVIEWS | IMMUNOLOGY
VOLUME 14 | SEPTEMBER 2014 © 2014 Macmillan Publishers Limited. All rights reserved
