Ever found yourself out of sync with normal sleep patterns after late nights or working a night shift? It could be you’re experiencing what scientists call social jet lag^[1].

The term describes the misalignment between our internal body clock (circadian rhythm) and our social schedule.

Social jet lag associated with irregular sleep patterns and inconsistent exposure to daylight is increasingly common, and has been linked with a weakened immune system^[2].

Disruption of our circadian rhythms through shift work, for example, has been shown to have a negative impact^[3] on our ability to fight infections.

These observations reinforce the idea that maintaining a robust circadian rhythm through regular exposure to daylight supports a healthy immune system.

But how does the immune system know when it’s daytime? That is precisely what our research, published today in Science Immunology^[4], has uncovered. Our findings could eventually deliver benefits for the treatment of inflammatory conditions.

First responders to infection

Circadian rhythms are a fundamental feature of all life on Earth. Believed to have evolved some 2.5 billion years ago, they enable organisms to adapt to challenges associated with the 24-hour solar day.

At the molecular level, these circadian rhythms are orchestrated through a genetically encoded multi-component time keeper called a circadian clock. Almost all cells are known to have the components for a circadian clock. But how they function within different cell types to regulate their behaviour is very poorly understood.

In the laboratory, we use zebrafish – small freshwater fish commonly sold in pet stores – as a model organism to understand our immune response to bacterial infection.

We use larval zebrafish because their genetic makeup and immune system are similar to ours. Also, they have transparent bodies, making it easy to observe biological processes under the microscope.

We focus on an immune cell called a “neutrophil^[5]”, a type of white blood cell. We’re interested in these cells because they specialise in killing bacteria, are first responders to infection, and are the most abundant immune cell in our bodies.

Because they are very short-lived cells, neutrophils isolated from human blood are notoriously difficult to work with experimentally. However, with transparent larval zebrafish, we can film them to directly observe how these cells function, within a completely intact animal.

Cells can tell if it’s daytime

Our initial studies showed the strength of immune response to bacterial infection peaked during the day, when the animals are active.

We think this represents an evolutionary response that provides both humans and zebrafish a survival advantage. Because diurnal animals such as humans and zebrafish are most active during daylight hours, they are more likely to encounter bacterial infections.

This work made us curious to know how this enhanced immune response was being synchronised with daylight. By making movies of neutrophils killing bacteria at different times of the day, we discovered they killed bacteria more efficiently during the daytime than at night.

We then genetically edited neutrophils to turn off their circadian clocks by carefully removing specific clock components. This is an approach similar to removing important cogs from an analogue clock so it doesn’t tick anymore.

This led to the discovery that these important immune cells possess an internal light-regulated circadian clock that alerts the cells to daytime (similar to an alarm clock). This boosts their ability to kill bacteria.

Our next challenge is to understand exactly how light is detected by neutrophils, and whether human neutrophils also rely on this internal timing mechanism to regulate their antibacterial activity.

We’re also curious to see if this killing mechanism is restricted to certain types of bacteria, such as those we’re more likely to encounter during the day. Or is it a more general response to all infectious threats (including viral infections)?

This research unlocks the potential for developing drugs that target the neutrophil circadian clock to regulate the cells’ activity. Given neutrophils are the first and most abundant immune cells to be recruited to sites of inflammation, the discovery has very broad implications for many inflammatory conditions.

The research described here was led by PhD candidates Lucia Du and Pramuk Keerthisinghe, and was a collaboration between the Hall laboratory and the Chronobiology Research Group, led by Guy Warman and James Cheeseman, at the University of Auckland’s Faculty of Medical and Health Sciences.

References

1. ^{^} social jet lag (sleepcycle.com)
2. ^{^} linked with a weakened immune system (pubmed.ncbi.nlm.nih.gov)
3. ^{^} shown to have a negative impact (www.cidrap.umn.edu)
4. ^{^} published today in Science Immunology (doi.org)
5. ^{^} neutrophil (pmc.ncbi.nlm.nih.gov)