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Circadian control of the immune system

Key Points

  • Circadian rhythms are endogenous oscillations in organisms of 24 hours in length that exist in virtually all cells.

  • The number of circulating leukocytes in the blood oscillates in a manner according to the phase of physical activity of the organism. Generally, the peak occurs during the resting phase.

  • In contrast to the peak number of circulating leukocytes, leukocyte recruitment to tissues occurs preferentially during the active phase of the organism. It is mediated by the in-phase expression of cell adhesion molecules and chemokines.

  • The response of an organism to acute inflammatory insults exhibits circadian oscillations. This is probably due to the circadian regulation of leukocyte trafficking, of the expression of pathogen-sensitive receptors and of the phagocytic activity of leukocytes.

  • Chronic diseases exhibit circadian exacerbations in their symptoms or presentations, which has been linked to an exaggeration of the circadian expression of pro-inflammatory mediators.

  • Circadian rhythms should be taken into account when harvesting human tissue samples and in experimental settings using preclinical animal models. In addition, chronopharmacology holds great promise to provide benefits for clinical care in the future.

Abstract

Circadian rhythms, which have long been known to play crucial roles in physiology, are emerging as important regulators of specific immune functions. Circadian oscillations of immune mediators coincide with the activity of the immune system, possibly allowing the host to anticipate and handle microbial threats more efficiently. These oscillations may also help to promote tissue recovery and the clearance of potentially harmful cellular elements from the circulation. This Review summarizes the current knowledge of circadian rhythms in the immune system and provides an outlook on potential future implications.

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Figure 1: The molecular clock and entrainment and synchronization.
Figure 2: Rhythms in immune cell function.
Figure 3: Contributing factors in circadian disease onset.

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Acknowledgements

Our work was supported by grants from the US National Institutes of Health (R01 HL097700, DK056638, HL097819, HL116340 and HL069438) to P.S.F., from the German Academic Exchange Service (DAAD) to C.S. and from the Japan Society for the Promotion of Science to Y.K.

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Correspondence to Christoph Scheiermann or Paul S. Frenette.

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Glossary

Sympathetic nerves

Nerves that belong to the sympathetic nervous system (SNS), which together with the parasympathetic nervous system makes up the autonomic nervous system. The SNS is under involuntary control and, among other functions, acts to mobilize the body's fight-or-flight response.

Zeitgeber

(German for 'time giver'). An environmental cue, such as light, food or temperature, that synchronizes the endogenous rhythm of an organism to the Earth's 24-hour light–dark cycle.

Rest–activity cycle

A species-specific rhythm determined by diurnal (in humans) or nocturnal (in rodents) periods of activity followed by times of rest.

Retinohypothalamic tract

A photic input pathway that connects photosensitive retinal ganglion cells directly to the suprachiasmatic nuclei of the hypothalamus.

Suprachiasmatic nuclei

A pair of nuclei (each consisting of approximately 10,000 highly interconnected neurons) that are located in a small region of the hypothalamus, above the optic chiasm, from where they receive environmental light input through the retinohypothalamic tract.

Hypothalamic–pituitary–adrenal axis

(HPA axis). The HPA axis consists of a complex set of input and feedback mechanisms between the hypothalamus, the pituitary gland and the adrenal gland. It is a major part of the neuroendocrine system.

Diurnal

A pattern that occurs during the day, in contrast to nocturnal.

Acrophase

The time at which the peak of a rhythm occurs.

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Scheiermann, C., Kunisaki, Y. & Frenette, P. Circadian control of the immune system. Nat Rev Immunol 13, 190–198 (2013). https://doi.org/10.1038/nri3386

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