An epithelial circadian clock controls pulmonary inflammation and glucocorticoid action

Abstract

The circadian system is as 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 that are 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 bacterial 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. In clock-gene disrupted mice the synthetic glucocorticoid dexamethasone loses anti-inflammatory efficacy. We now define a regulatory mechanism that links the circadian clock and glucocorticoid hormones to control both time-of-day variation and also the magnitude of pulmonary inflammation and responses to bacterial infection.

Simulated Night Shift Disrupts Circadian Rhythms of Immune Functions in Humans

“…These immune cell clocks could act in two ways: by regulating the expression of molecules important for the synthesis and secretion of cytokines by these cells and by gating the response to the regulatory effects of cues from the central clock. A local direct regulation of immune cell functions (25,28) and a gating of the response to systemic cues (14,58,59) were shown to occur in rodents. However, we cannot exclude that the shift in the sleep-wake/feeding cycle might have contributed, to some extent, to the changes observed in the cytokine-release rhythm.…”

Disruption of Sirtuin 1–Mediated Control of Circadian Molecular Clock and Inflammation in Chronic Obstructive Pulmonary Disease

“…Hence, clock dysfunction in the lungs may explain increased COPD exacerbations in patients presenting at night and in the early morning hours when lung function is low (1). These effects may be due to circadian disruption in peripheral tissues and/or uncoupling between peripheral oscillators and the master clock located in the suprachiasmatic nucleus of the hypothalamus (5)(6)(7)(8). By examining the direct effects of smoking and COPD on molecular clock gene expression in peripheral oscillators, we can dissect the impact of environmental stress on cell-autonomous clocks and begin to describe the mechanism linking clock disruption to enhanced inflammatory responses (9).…”

“…This suggests the involvement of the SIRT1-BMAL1 signaling pathway in CS-induced lung inflammation and circadian dysfunction. Accumulating evidence indicates that monocytes/ macrophages and epithelial cells show a daily variation of inflammatory immune responses to environmental stress (5,(17)(18)(19). However, it is not known whether circadian clock function is disrupted in smokers and patients with COPD and whether these responses can be regulated by SIRT1.…”

Impact of timing of elective abdominal surgery on postoperative liver function

“…For example, the circadian rhythm observed in glucocorticoid hormones have been found to be linked with the magnitude of pulmonary inflammation. 7 In addition, the periodic variations in levels of melatonin indirectly affects inflammatory reaction. 8 Mattana et al reported that patients who underwent HD late in the day had relatively higher levels of potassium and phosphorus than those dialyzed earlier in the day.…”