Circadian Clocks, Stress, and Immunity

Abstract

In mammals, molecular circadian clocks are present in most cells of the body, and this circadian network plays an important role in synchronizing physiological processes and behaviors to the appropriate time of day. The hypothalamic-pituitary-adrenal endocrine axis regulates the response to acute and chronic stress, acting through its final effectors - glucocorticoids - released from the adrenal cortex. Glucocorticoid secretion, characterized by its circadian rhythm, has an important role in synchronizing peripheral clocks and rhythms downstream of the master circadian pacemaker in the suprachiasmatic nucleus. Finally, glucocorticoids are powerfully anti-inflammatory, and recent work has implicated the circadian clock in various aspects and cells of the immune system, suggesting a tight interplay of stress and circadian systems in the regulation of immunity. This mini-review summarizes our current understanding of the role of the circadian clock network in both the HPA axis and the immune system, and discusses their interactions.

Keywords: HPA axis; circadian clock; glucocorticoids; immune system; stress.

Figure 1

The rhythmic control of the HPA axis is regulated at several levels. The master clock residing in the suprachiasmatic nucleus (SCN) is synchronized by light information received via the retinohypothalamic tract from the eye in order to exert autonomic (ANS) and hormonal influence on the clocks and rhythms of downstream tissues of the body. In addition to the direct innervation of the adrenal, the SCN influences the paraventricular nucleus (PVN) to secrete corticotropin-releasing hormone (CRH) and arginine vasopressin (AVP), which reach the pituitary via the blood portal system to stimulate secretion of adrenocorticotropic hormone (ACTH), which activates production and release of glucocorticoids. In addition, local adrenal clocks are thought to regulate responsiveness to ACTH in a circadian fashion. The baseline circadian rhythm of circulating glucocorticoids peaks just before the beginning of the active phase (day in humans and night in rodents). Stress-induced stimulation of the HPA axis acts via afferent signals from the limbic forebrain and brainstem to the PVN. Inset: the core transcriptional–translational feedback loop (TTL) that makes up the molecular circadian clockwork. In the positive arm of the clock, CLOCK or NPAS2 form a complex with BMAL1 and bind to E-Box elements in the gene promotors of PERs and CRYs, which make up the negative arm and act to inhibit the activity of CLOCK–BMAL1 or NPAS2–BMAL1, with a cycle of roughly 24 h. For further detail, see the main text.

Figure 2

Circadian clocks in HPA axis-immune system crosstalk. Immune cells can activate the HPA axis via cytokines such as tumor necrosis factor-alpha (TNF-α) and interleukins (IL-1/6) at the level of the paraventricular nucleus (PVN) of the hypothalamus as well as at the pituitary and adrenal, stimulating the production of glucocorticoids. Glucocorticoids in turn act on the receptors on the surface or in the cytoplasm of immune cells to suppress the induction of pro-inflammatory responses, and to promote a shift from T helper cell type 1 (Th1) toward T helper cell type 2 (Th2)-mediated humoral immunity. This inhibits the production of pro-inflammatory cytokines, while promoting the production of anti-inflammatory cytokines, such as interleukin-4, interleukin-10, and interleukin-13 (IL-4/10/13) by various immune cells. In addition, ACTH exerts direct anti-inflammatory and immune-modulating effects via the melanocortin system. CRH, corticotropin-releasing hormone; AVP, arginine vasopressin; DC, dendritic cell; MΦ, macrophage.