Editors' ChoiceInflammation

Timing Responses to Infection

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Sci. Signal.  12 Aug 2014:
Vol. 7, Issue 338, pp. ec212
DOI: 10.1126/scisignal.2005780

Human lung diseases characterized by chronic inflammation and tissue damage often show diurnal variation in the severity of symptoms. Circadian rhythms in biological functions are determined by a centrally generated pattern of neural and endocrine rhythms that acts systemically and by cell-intrinsic patterns in peripheral tissues. Bronchiolar club cells (also known as Clara cells) play a role in immune functions in the lung (see Thompson et al.). Gibbs et al. discovered that diurnal differences in the response to lung infections were driven by circadian rhythms of cytokine release from bronchiolar club cells. Mice challenged with aerosolized lipopolysaccaharide (LPS) or infected with Streptococcus pneumoniae at different times of the day had different numbers of neutrophils in the lung and produced different amounts of several cytokines. Conditional knockout of the gene encoding the circadian transcription factor BMAL1 in bronchiolar club cells, but not in circulating myeloid immune cells, disrupted the circadian inflammatory response to LPS, resulting in an overall increase in the number of neutrophils in the lung. The expression of the mRNA encoding the neutrophil-attracting chemokine CXCL5 had circadian differences in expression in bronchiolar epithelial cells. Knockout of Bmal1 in bronchiolar club cells abolished circadian oscillation and increased the overall expression of Cxcl5. Global knockout of Cxcl5 decreased the inflammatory response to LPS in the lung. Knockout of Bmal1 in bronchiolar club cells disrupted the circadian regulation of glucocorticoid receptor (GR) binding and activation of the promoter of Cxcl5, and adrenalectomy, which reduces the amount of circulating corticosterone (a glucocorticoid with circadian oscillations in abundance), reduced the bronchiolar expression of Cxcl5 and lung inflammation in response to LPS. Treating mice with the anti-inflammatory drug dexamethasone, which activates the GR, reduced LPS-induced inflammation in wild-type mice but not in mice with Bmal1 knockout in bronchiolar club cells. Thus, a combination of systemic and cell-intrinsic circadian mechanisms governs the diurnal differences in lung inflammatory responses.

J. Gibbs, L. Ince, L. Matthews, J. Mei, T. Bell, N. Yang, B. Saer, N. Begley, T. Poolman, M. Pariollaud, S. Farrow, F. DeMayo, T. Hussell, G. S. Worthen, D. Ray, A. Loudon, An epithelial circadian clock controls pulmonary inflammation and glucocorticoid action. Nat. Med. 20, 919–926 (2014). [PubMed]

A. A. R. Thompson, S. R. Walmsley, M. K. B. Whyte, A local circadian clock calls time on lung inflammation. Nat. Med. 20, 809–811 (2014). [PubMed]