Researchers discovered that the function of a group of immune cells is directly controlled by the brain’s circadian clock


It is well known that individuals who work night shifts or travel often across different time zones have a higher tendency to become overweight and suffer from gut inflammation.

The underlying cause for this robust phenomenon has been the subject of many studies that tried to relate physiological processes with the activity of the brain’s circadian clock, which is generated in response to the daylight cycle.

Now, the group of Henrique Veiga-Fernandes, at the Champalimaud Centre for the Unknown in Lisbon, Portugal, discovered that the function of a group of immune cells, which are known to be strong contributors to gut health, is directly controlled by the brain’s circadian clock.

Their findings were published today in the scientific journal Nature.

“Sleep deprivation, or altered sleep habits, can have dramatic health consequences, resulting in a range of diseases that frequently have an immune component, such as bowel inflammatory conditions,” says Veiga-Fernandes, the principal investigator.

“To understand why this happens, we started by asking whether immune cells in the gut are influenced by the circadian clock.

The big clock and the little clock

Almost all cells in the body have an internal genetic machinery that follows the circadian rhythm through the expression of what are commonly known as “clock genes.”

The clock genes work like little clocks that inform cells of the time of day and thereby help the organs and systems that the cells make up together, anticipate what is going to happen, for instance if it’s time to eat or sleep.

Even though these cell clocks are autonomous, they still need to be synchronized in order to make sure that “everyone is on the same page.”

“The cells inside the body don’t have direct information about external light, which means that individual cell clocks can be off,” Veiga-Fernandes explains.

“The job of the brain’s clock, which receives direct information about daylight, is to synchronize all of these little clocks inside the body so that all systems are in synch, which is absolutely crucial for our wellbeing.”

Among the variety of immune cells that are present in the intestine, the team discovered that Type 3 Innate Lymphoid Cells (ILC3s) were particularly susceptible to perturbations of their clock genes.

“These cells fulfill important functions in the gut: they fight infection, control the integrity of the gut epithelium and instruct lipid absorption,” explains Veiga-Fernandes.

“When we disrupted their clocks, we found that the number of ILC3s in the gut was significantly reduced. This resulted in severe inflammation, breaching of the gut barrier, and increased fat accumulation.”

These robust results drove the team to investigate why is the number of ILC3s in the gut affected so strongly by the brain’s circadian clock.

The answer to this question ended up being the missing link they were searching for.

It’s all about being in the right place at the right time

When the team analyzed how disrupting the brain’s circadian clock influenced the expression of different genes in ILC3s, they found that it resulted in a very specific problem: the molecular zip-code was missing!

It so happens that in order to localize to the intestine, ILC3s need to express a protein on their membrane that works as a molecular zip-code.

This ‘tag’ instructs ILC3s, which are transient residents in the gut, where to migrate. In the absence of the brain’s circadian inputs, ILC3s failed to express this tag, which meant they were unable to reach their destination.

According to Veiga-Fernandes, these results are very exciting, because they clarify why gut health becomes compromised in individuals who are routinely active during the night.

“This mechanism is a beautiful example of evolutionary adaptation,” says Veiga-Fernandes.

“During the day’s active period, which is when you feed, the brain’s circadian clock reduces the activity of ILC3s in order to promote healthy lipid metabolism.

But then, the gut could be damaged during feeding. So after the feeding period is over, the brain’s circadian clock instructs ILC3s to come back into the gut, where they are now needed to fight against invaders and promote regeneration of the epithelium.”

“It comes as no surprise then,” he continues, “that people who work at night can suffer from inflammatory intestinal disorders.

It has all to do with the fact that this specific neuro-immune axis is so well-regulated by the brain’s clock that any changes in our habits have an immediate impact on these important, ancient immune cells.”

This study joins a series of groundbreaking discoveries produced by Veiga-Fernandes and his team, all drawing new links between the immune and nervous systems.

“The concept that the nervous system can coordinate the function of the immune system is entirely novel.

It has been a very inspiring journey; the more we learn about this link, the more we understand how important it is for our wellbeing and we are looking forward to seeing what we will find next,” he concludes.

With the discovery of an innate counterpart of the T lymphocytes mirroring key aspect of their phenotype and function, the innate lymphoid cells (ILCs) have forced immunologists to rethink the immunological architecture that confers immune protection. Despite recent evidence that ILCs can be mobilized from blood (12), ILCs are considered to mainly reside within tissues (3).

Their activity is not modulated by antigen-specific receptors but rather through a complex integration of cytokines, alarmins, and physiological signals derived from their micro-environment.

Divided in 3 main groups, group 1 ILCs (ILC1s), group 2 ILCs (ILC2s), and group 3 ILCs (ILC3s) are associated with T helper (Th) 1, Th2, and Th17 functions, respectively, while the natural killer (NK) cells are analogous to the CD8+ cytotoxic T cells.

ILCs express particular sets of receptors encoded by specific transcriptomic signatures that are imprinted in a tissue-specific manner and therefore ILCs are well equipped to sense host-derived signals (Figure 1) (5).

Constitutive sensing and integration of these endogenous signals are essential to ILC activity and maintenance of tissue homeostasis.

Dysregulation of ILC responses lead to the development of inflammation. ILC1s are mainly involved in the early protection against virus (6) and bacteria (78) through the secretion of interferon-gamma (IFN-γ) and granulocyte-macrophage colony-stimulating factor (GM-CSF), however their dysregulation in adipose tissues leads to the development of metabolic disorders and obesity (9).

ILC2s are an early source of interleukin (IL)-5 and IL-13 (1012). ILC2 activity allows the emergence to type 2 immune responses characterized by goblet cell differentiation, recruitment of eosinophils, basophils, and mast cells which is critical for protection against infection with helminths and viruses but, when uncontrolled, also drive allergic responses and metabolic disorder (1315).

ILC3s produce IL-22 in the gut to protect against intestinal inflammation (1618). In this review we propose that physiological signals are integrated by ILCs and modulate their constitutive activity in a tissue- and time-specific manner.

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Figure 1
Heatmap shows the RNA expression of the indicated receptors among different immune populations. The data have been extracted from Immunological Genome Project ( (4). Name of each population extracted from ImmGen database are indicated on top of the heatmap.

Vasoactive Intestinal Peptide (VIP)

VIP is a neuropeptide expressed throughout the nervous system and has been found in neurons that innervate the lung and gut mucosa (26).

VIP is involved in number of physiological processes, including coordinating gastrointestinal motility, mucus, and enzymatic secretions in response to feeding, synchronizing the central circadian rhythm (27) and also skews the differentiation of T cells toward Th2 and T regulatory cells (2829).

Enteric and lung ILC2s stimulated with VIP through VIP receptor type 2 (VPAC2) promotes a type 2 response.

The circadian release of VIP in response to feeding induces a rhythmic expression of IL-5 by ILC2s (Figure 2), resulting in increased systemic eosinophil numbers in a circadian manner (30).

IL-5 stimulates the production of VIP by acting directly on nociceptors, creating an inflammatory signal loop that promotes allergic inflammation (31).

Noxious environmental respiratory stimuli, such as capsaicin or OVA peptide challenge, induces bronchial hyperresponsiveness and airway inflammation through the activation of lung NaV1.8+ nociceptor. Ablation of NaV1.8+ nociceptor reduces the activation of lung resident ILC2 and Th2 cells, thus reducing bronchial hyperresponsiveness. Administering VPAC2 antagonist leads to decreased ILC2 activation, decreased expression of inflammatory marker ST2 and decreased production of IL-5 and IL-13 (31) (Figure 2). This positive feedback loop between sensory nociceptors and ILC2s may be a mechanism to prime and enhance the sensitivity of sensory nociceptors to environmental stimuli.

More information: Light-entrained and brain-tuned circadian circuits regulate ILC3 and gut homeostasis, Nature (2019). DOI: 10.1038/s41586-019-1579-3 ,

Journal information: Nature
Provided by Champalimaud Centre for the Unknown


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