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Lung Inflammation Clocks In and Out

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Science Translational Medicine  20 Aug 2014:
Vol. 6, Issue 250, pp. 250ec143
DOI: 10.1126/scitranslmed.3010123

Circadian rhythms can serve as a clock that helps govern important physiological functions, including how we control inflammation and fight infections. Disruptions of day-night circadian patterns such as shift work or jet lag can alter this clock into something more reminiscent of Salvador Dali, increasing susceptibility to infections. Many inflammatory lung disorders such as chronic obstructive pulmonary disease (COPD) and asthma show time-of-day variation in symptomology and disease severity. Gibbs and colleagues found that the epithelial club (Clara) cells lining the pulmonary airways have their own clock that controls neutrophilic lung inflammation.

The authors found that the circadian clock regulates the inflammatory responses to inhaled endotoxin in the lung in a manner that is different from systemic endotoxin challenges. With a focus on the local pulmonary inflammatory response, they generated animals with the clock gene Bma1 conditionally deleted in the pulmonary epithelium and found that the lung tissue’s baseline circadian rhythm was disrupted. Furthermore, the loss of the pulmonary epithelium clock resulted in more severe neutrophilic lung inflammation in response to endotoxin and Streptococcus pneumoniae bacterial infection.

CXCL5 is a chemokine that attracts neutrophils to migrate into the lung. The authors found that the circadian regulation of neutrophilic inflammation was impaired in the absence of CXCL5. Endogeneous glucocorticoids, which are regulated by the adrenal gland–derived circadian clock signals, subsequently rhythmically suppressed CXCL5 and the associated inflammation. The effects of glucocorticoid on its receptor were substantially disrupted without the local clock gene Bma1. Adrenolectomy eliminated the glucocorticoid signals, disrupting the circadian variation of CXCL5 and neutrophilic infiltration. They concluded that the actions of glucocorticoids are under the control of the local pulmonary clock.

These findings have important implications in infections and in diseases that rely on the use of glucocorticoids. This could potentially explain the ineffectiveness of glucocorticoids in neutrophil-associated chronic lung diseases such as COPD and steroid-resistant asthma. The pulmonary responses to environmental insults need to be carefully balanced by controlling persistent inflammation so as to avoid excessive local tissue damages. One might be able to target the locally operating circadian rhythm in the lung in order to control the timing of inflammation and innate immunity.

J. Gibbs et al., An epithelial circadian clock controls pulmonary inflammation and glucocorticoid action. Nat. Med. 20, 919–926 (2014). [Abstract]

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