Endocrine Abstracts

The circadian clock is a key regulator of immune responses. Both circulating and resident immune cells possess intrinsic timers, which act to impart time-of-day variation in their function. It is now becoming evident that the circadian clock is also critically involved in regulating the function of endogenous anti-inflammatory glucocorticoid hormones. Consequently, we see variation in an animal’s inflammatory responses dependent on the time the stimulus was delivered. This can vary to such an extent, it can affect survival outcome.

We have demonstrated that the time of day at which a 20 min burst of aerosolized lipopolysaccharide is applied strongly influences the amplitude of the resultant pulmonary neutrophilic response. Exposing mice at the start of the day (lights on) causes significantly greater transcription of the cytokine cxcl5, resulting in significantly increased recruitment of neutrophils to the lung. Ablation of the circadian clock in Club cells (bronchiolar epithelial cells critical for maintaining pulmonary timing and the major source of CXCL5) not only abolishes this time-of-day gating in response amplitude, but causes a dramatic increase in CXCL5 production and thus neutrophil recruitment. This is a consequence of reduced binding of the glucocorticoid receptor (GR) to the glucocorticoid response element on the cxcl5 promoter. We conclude from this that the intrinsic clock within cells regulates the anti-inflammatory action of endogenous glucocorticoid signals via the GR.

This interaction between the circadian clock and GR has significant consequences on the action of applied therapeutic glucocorticoids. Indeed, the repressive action of applied glucocorticoids to pulmonary inflammation varies dependent on time-of-day. With subsets of inflammatory cytokines being responsive to dexamethasone repression only at certain phases of the clock. These findings have implications in the use of therapeutic glucocorticoids, and suggest that effective delivery of anti-inflammatory glucocorticoids is a matter of timing.