Glucocorticoids Regulate Circadian Rhythm of Innate and Adaptive Immunity

Akihiro Shimba, Koichi Ikuta, Akihiro Shimba, Koichi Ikuta

Abstract

Animals have evolved circadian rhythms to adapt to the 24-h day-night cycle. Circadian rhythms are controlled by molecular clocks in the brain and periphery, which is driven by clock genes. The circadian rhythm is propagated from the brain to the periphery by nerves and hormones. Glucocorticoids (GCs) are a class of steroid hormones produced by the adrenal cortex under the control of the circadian rhythm and the stress. GCs have both positive and negative effects on the immune system. Indeed, they are well known for their strong anti-inflammatory and immunosuppressive effects. Endogenous GCs inhibit the expression of inflammatory cytokines and chemokines at the active phase of mice, regulating the circadian rhythm of tissue inflammation. In addition, GCs induce the rhythmic expression of IL-7R and CXCR4 on T cells, which supports T cell maintenance and homing to lymphoid tissues. Clock genes and adrenergic neural activity control the T cell migration and immune response. Taken together, circadian factors shape the diurnal oscillation of innate and adaptive immunity. Among them, GCs participate in the circadian rhythm of innate and adaptive immunity by positive and negative effects.

Keywords: IL-7 receptor; T cell; circadian rhythm; glucocorticoid; inflammatory cytokine.

Copyright © 2020 Shimba and Ikuta.

Figures

FIGURE 1
FIGURE 1
Glucocorticoids induce T cell migration into spleen from blood and enhance immune response at night by expression of IL-7R and CXCR4. Zeitgeber time (ZT) is a unit of cycle consisted of 12 h light/12 h dark phase. ZT0 is defined as the time when light on and ZT12 is defined as the time when light off. At the rest phase (ZT4) in mice, more T cells circulate in peripheral blood. At the onset of the active phase, the adrenal cortex releases glucocorticoids, which induce IL-7R and CXCR4 expression on T cells. At the active phase (ZT16), the elevated receptors trigger T cell migration into second lymphoid tissues such as spleen, lymph nodes, and Peyer’s patches. The T cell accumulation induces a stronger immune response by effector CD8 T cells and follicular helper T (Tfh) cells against bacterial infections and soluble antigens.
FIGURE 2
FIGURE 2
Circadian control of immunity by glucocorticoids and other factors. At the active phase, glucocorticoids (GCs), and BMAL1 suppress CXCL5 expression in lung epithelium and suppress neutrophil recruitment. In addition, GCs alleviate the endotoxin shock stimulated by LPS and the allergic response mediated by mast cells in skin and lung. As immune-enhancing effects, GCs, BMAL1, and β2 adrenergic receptor (β2AR) trigger T cell migration to and retention in lymphoid tissues by enhancing the expression and function of chemokine receptors at the active phase. This accumulation augments T cell-mediated immunity such as anti-bacterial response, B cell activation, and autoimmunity.

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