Connection between circadian rhythms and immune responses revealed

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Researchers in Switzerland compiled studies, predominantly in mice, that looked at the connection between circadian rhythms and immune responses.

For example, studies showed that adaptive immune responses–in which highly specialized, pathogen-fighting cells develop over weeks–are under circadian control.

This is “striking,” says senior author Christoph Scheiermann, an immunologist at the University of Geneva, “and should have relevance for clinical applications, from transplants to vaccinations.”

The body reacts to cues such as light and hormones to anticipate recurring rhythms of sleep, metabolism, and other physiological processes.

In both humans and mice, the numbers of white blood cells also oscillate in a circadian manner, raising the question of whether it might be possible one day to optimize immune response through awareness and utilization of the circadian clock.


The term circadian rhythm (from the latin circa diem, which means ‘for about a day’) was coined by Halberg to describe endogenous oscillations in organisms that were observed in approximate association with the earth’s daily rotation cycle1.

Circadian rhythms are hypothesized to have evolved in aerobic organisms to anticipate changes of environmental oxygen levels driven by photosynthetic bacteria and the solar cycle2. T

hey present competitive advantages to organisms, by handling energy supply more efficiently and enhancing their ability to survive respiration-associated cycles of oxidative stress.

In mammals, it has been estimated that approximately 10% of the genome is under circadian control34.

Over the past fifteen years, evidence for circadian oscillations of components of the immune system has emerged as an integral regulator that has the potential to impact disease onset and therapies56.

Recent studies suggest that cyclical recruitment of immune cells to tissues can affect disease.

Rhythms in tissues appear to be synchronized globally while acting locally via sympathetic nerves to orchestrate tissue-specific oscillations in the expression of adhesion molecules and chemokines by endothelial cells7.

These rhythms are matched by endogenous oscillations in the expression of pro-migratory factors by immune cells, thus increasing the likelihood of their homing to tissues at specific stages in the circadian cycle.

Additional data point to the importance of circadian expression of components of the innate immune system for the onset of inflammatory diseases89.

In humans, autonomous circadian rhythms span approximately 24h in length and need to be synchronized to overlap with the daily rotational cycle of the earth.

The alignment of an organisms’ endogenous circadian rhythm to an external rhythm is called entrainment.

The light patterns represent the principal environmental cue or zeitgeber (German for ‘time giver’10) to align the daily oscillations of the organism. Light anchors the organism in its geophysical time by setting the rest–activity cycle. In addition, it is indirectly responsible for the time of food intake, which is itself another powerful entrainer of rhythm11.

The central clock

In opaque organisms such as mammals, light is processed through the eye and is transmitted via the retinohypothalamic tract to suprachiasmatic nuclei (SCN) neurons in the hypothalamus12.

The SCN are the central clock, the master pacemaker of the organism13. Recent excellent reviews have provided a detailed overview of the molecular components comprising the clock11,121415; the reader is encouraged to consult them as these concepts will only be briefly discussed here.

At the molecular level, the clock consists of multiple sets of transcription factors that result in autoregulatory transcription-translation feedback loops (TTFLs) (Fig. 1a).

Transcription of the core clock genes BMAL1 (brain and muscle Arnt-like protein 1) and CLOCK (circadian locomotor output cycles kaput), or its related gene NPAS2 (neuronal PAS domain containing protein-2; mainly expressed in the forebrain), results in the heterodimerization of the BMAL1–CLOCK complex in the cytoplasm, triggering its nuclear translocation where it binds to canonical Enhancer Box (E-Box)-sequences of clock controlled genes (CCGs, Box 1)16.

In addition, BMAL1 and CLOCK promote their own repression by inducing the expression of their negative regulators PER (period) and CRY (cryptochrome)

The PER–CRY heterodimer translocates to the nucleus and interacts with BMAL1–CLOCK to inhibit transcription. The cycle starts anew when expression of PER–CRY wanes due to reduced BMAL1–CLOCK levels.

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Figure 1
a) The molecular clock.
Transcription of the core clock genes Bmal1 and Clock (or its related gene Npas2, not shown) results in their heterodimerization in the cytoplasm and ensuing nuclear translocation. These helix-loop-helix transcription factors bind to canonical E-Box sequences (CACGTG) of clock-controlled genes (CCGs), driving circadian processes and their own expression. In addition, the expression of negative (PER and CRY) as well as positive (retinoic acid-related orphan receptor (ROR)) regulators of this cycle is induced. The PER/CRY complex represses binding of BMAL1–CLOCK to target genes, whereas ROR binding to ROR responsive elements (ROREs) in the Bmal1 promoter induces expression. After a period of time, the PER/CRY complex is degraded and BMAL1–CLOCK activates another transcription cycle. A second autoregulatory feedback loop is induced by transcription of REV-ERBα and REV-ERBβ (encoded by Nr1d1 and Nr1d2). The REV-ERBα–REV-ERBβ complex represses Bmal1 transcription and competes with ROR for binding of ROREs. While this pathway stabilizes the clock it can also directly drive circadian rhythms. The molecular clock does not only depend on transcriptional/translational feedback but is also regulated by rhythms in post-translational modifications of proteins such as oxidation cycles of peroxiredoxins (PRXox(idized)/PRXred(uced)) as well as NADPH and NADH, the latter of which can modulate the binding of the BMAL1/CLOCK complex to DNA directly.
b) Entrainment and synchronization.
Circadian rhythms are entrained by external cues, of which light is a major contributor. Light is processed via the retina, leading to synchronization of rhythms in hypothalamic suprachiasmatic nuclei, which comprise the master clock of the organism. From here, humoral and neural output systems modulate clocks in peripheral tissues via the hypothalamic-pituitary-adrenal (HPA) axis, setting a common phase. Release of adrenocorticotropic hormone (ACTH) from the pituitary gland likely cooperates with the sympathetic nervous system (SNS) to regulate rhythmic release of hormones (glucocorticoids, epinephrine and norepinephrine) from the adrenal glands. In addition the SNS directly innervates tissues, and can modulate circadian rhythms locally via cyclical release of norepinephrine from nerve varicosities.

The role of the nuclear receptors REV-ERBα (encoded by Nr1d1) and REVERBβ (encoded by Nr1d2), which were previously thought to form an accessory feedback loop that stabilizes the clock, has been recently refined as a more integral part of this pathway capable of driving circadian rhythms17

Nr1d1−/−Nr1d2−/− mice showed a complete loss of circadian rhythm, comparable to other clock-deficient strains (such as Per1−/−Per2−/− and Cry1−/−Cry2−/−)17.

Although the transcriptional regulation of these clock genes has long been the paradigm for the control of circadian rhythms, recent surprising observations in red blood cells and algae have revealed that circadian oscillations can exist solely due to rhythmic modifications at the posttranslational level1819.

These data indicate that regulation of the clock occurs at many different levels, thereby increasing the stability of the system.


In separate studies that compared immune cell time-of-day rhythms under normal conditions, inflammation, and disease, researchers found that:

  • Heart attacks in humans are known to strike most commonly in the morning, and research suggests that morning heart attacks tend to be more severe than at night. In mice, the numbers of monocytes–a type of white blood cell that fights off bacteria, viruses, and fungi–are elevated in the blood during the day. At night, monocytes are elevated in infarcted heart tissue, resulting in decreased cardiac protection at that time of day relative to morning.
  • The ability of immune cells to fight atherosclerotic plaques can depend on CCR2–a chemokine protein linked to immune function and inflammation. CCR2 exhibits a daily rhythm in mice, peaking in the morning, and based on its influence on immune cells, can be followed to understand white blood cell behaviors in mouse models of atherosclerosis.
  • Parasite infections are time-of-day dependent. Mice infected with the gastrointestinal parasite Trichuris muris in the morning have been able to kill worms significantly faster than mice infected in the evening.
  • A bacterial toxin tied to pneumonia initiates an inflammatory response in the lungs of mice. Recruitment of immune cells during lung inflammation displays a circadian oscillation pattern. Separately, more monocytes can be recruited into the peritoneal cavity, spleen, and liver in the afternoon, thus resulting in enhanced bacterial clearance at that time.
  • Allergic symptoms follow a time-of-day dependent rhythmicity, generally worse between midnight and early morning. Hence, the molecular clock can physiologically drive innate immune cell recruitment and the outcomes of asthma in humans, or airway inflammation in mice–the review notes.
This shows a person sneezing into a tissue

In both humans and mice, the numbers of white blood cells also oscillate in a circadian manner, raising the question of whether it might be possible one day to optimize immune response through awareness and utilization of the circadian clock. The image is in the public domain.

“Investigating circadian rhythms in innate and adaptive immunity is a great tool to generally understand the physiological interplay and time-dependent succession of events in generating immune responses,” Scheiermann says.

“The challenge lies in how to channel our growing mechanistic understanding of circadian immunology into time-tailored therapies for human patients.”

Source:
Cell Press
Media Contacts: 
Carly Britton – Cell Press
Image Source:
The image is in the public domain.

Original Research: Open access
“Time-of-Day-Dependent Trafficking and Function of Leukocyte Subsets”. Robert Pick, Wenyan He, Chien-Sin Chen, Christoph Scheiermann.
Trends in Immunology. doi:10.1016/j.it.2019.03.010

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