In mammals, the master clock of the suprachiasmatic nuclei (SCN) and subordinate clocks found throughout the body coordinate circadian rhythms of behavior and physiology. We characterize the clock of the adrenal, an important endocrine gland that synchronizes physiological and metabolic rhythms. Clock gene expression was detected in the outer adrenal cortex prefiguring a role of the clock in regulating gluco- and mineral corticoid biogenesis. In Per2/Cry1 double mutant mice, which lack a circadian clock, hypothalamus/pituitary/adrenal axis regulation was defective. Organ culture and tissue transplantation suggest that the adrenal pacemaker gates glucocorticoid production in response to adrenocorticotropin (ACTH). In vivo the adrenal circadian clock can be entrained by light. Transcriptome profiling identified rhythmically expressed genes located at diverse nodes of steroid biogenesis that may mediate gating of the ACTH response by the adrenal clock.

SummaryLymphocytes circulate through lymph nodes (LN) in search for antigen in what is believed to be a continuous process. Here, we show that lymphocyte migration through lymph nodes and lymph occurred in a non-continuous, circadian manner. Lymphocyte homing to lymph nodes peaked at night onset, with cells leaving the tissue during the day. This resulted in strong oscillations in lymphocyte cellularity in lymph nodes and efferent lymphatic fluid. Using lineage-specific genetic ablation of circadian clock function, we demonstrated this to be dependent on rhythmic expression of promigratory factors on lymphocytes. Dendritic cell numbers peaked in phase with lymphocytes, with diurnal oscillations being present in disease severity after immunization to induce experimental autoimmune encephalomyelitis (EAE). These rhythms were abolished by genetic disruption of T cell clocks, demonstrating a circadian regulation of lymphocyte migration through lymph nodes with time-of-day of immunization being critical for adaptive immune responses weeks later.

ESSENTIAL POINTSThe daily rhythmicity of plasma glucocorticoid (GC) levels is a strong modulator of many physiological and psychological processes, although its functional significance is poorly understood.The suprachiasmic nuclei of the hypothalamus have been shown to harbor a molecular clock mechanism generating circadian rhythmicity in mammals, but the same mechanism is present in many peripheral tissues and elsewhere in the brain.Mineralocorticoid receptors and glucocorticoid receptors mediate the action of naturally occurring GC in complementary fashion.Optimal physiological effects of GC occur when the central signal that controls the rhythm of GC release and the peripheral rhythms in tissues expressing GC receptors are aligned.New studies suggest that misalignment of central and peripheral oscillators may increase the risk of disease, with adverse effects on the immune system, cardiovascular system and metabolism, among others prominent.Chronopharmacological strategies that attempt to normalize the rhythm of circulating GCs have potential to improve the treatment of a wide variety of physical and mental conditions.