Shift-work and irregular work schedules can cause several health-related issues and affect our defense against infection, according to new research from the University of Waterloo.
These health-related issues occur because the body’s natural clock, called the circadian clock, can be disrupted by inconsistent changes in the sleep-wake schedule and feeding patterns often caused by shift work. To study this, researchers at Waterloo developed a mathematical model to look at how a disruption in the circadian clock affects the immune system in fighting off illness.
“Because our immune system is affected by the circadian clock, our ability to mount an immune response changes during the day,” said Anita Layton, professor of Applied Mathematics, Computer Science, Pharmacy and Biology at Waterloo. “How likely are you to fight off an infection that occurs in the morning than midday?
The answer depends on whether you are a man or a woman, and whether you are among quarter of the modern-day labor force that has an irregular work schedule.”
The model is composed of the core clock genes, their related proteins, and the regulatory mechanism of pro- and anti-inflammatory mediators. By adjusting the clock, the models can simulate male and female shift-workers.
The results of these computer simulations conclude that the immune response varies with the time of infection. Model simulation suggests that the time before we go to bed is the “worst” time to get an infection.
That is the period of the day when our body is least prepared to produce the pro- and anti-inflammatory mediators needed during an infection. Just as importantly, an individual’s sex impacts the severity of the infection.
“Shift work likely affects men and women differently,” said Stéphanie Abo, a Ph.D. candidate in Waterloo’s Department of Applied Mathematics. “Compared to females, the immune system in males is more prone to overactivation, which can increase their chances of sepsis following an ill-timed infection.”
The study, Modeling the circadian regulation of the immune system: sexually dimorphic effects of shift work, authored by Waterloo’s Faculty of Mathematics’ Layton and Abo, was recently published in the journal PLoS Computational Biology.
Most organisms from bacteria to humans are equipped with an internal biological clock, known as a circadian clock—a network of molecular interactions generating biochemical oscillations with a near 24-hour period [1].
In mammals, the circadian timing system consists of almost as many clocks as there are cells, as most cells house self-sustained and autonomous circadian oscillators [1]. This coordination of rhythms with the diurnal cycle is under the control of a central synchronizer, the suprachiasmatic nucleus (SCN), located in the ventral hypothalamus [2]. The SCN receives direct photic input from the retina, produces rhythmic outputs and orchestrates local clocks in the brain and peripheral clocks throughout the body [3].
Peripheral clocks can be coordinated by systemic cues emanating from the SCN [1], and they can be synchronized also by external cues such as temperature, feeding schedules and light [3]. In particular, the circadian circuitry in the lungs is exquisitely sensitive to environmental factors and exposomes [4], including air pollutants [5], cigarette smoke [6, 7], shift work [8–10], jet lag [11, 12], pathogens [13, 14] and much more.
Of particular interest is the impact of circadian disruption on immune cell function, host defense and inflammation. The emerging picture is that the strength of the immune response varies throughout the day and that dysregulation of clock genes can lead to inflammatory disease or immunodeficiency [15].
Over the past decades, our societies have experienced rapid growth in the need for work in recurring periods other than traditional daytime periods. Research shows that shift work disrupts the natural sleep-wake cycle and feeding patterns [16], which may in turn cause serious health problems [17].
Here, we use mathematical modeling to study the effects of shift work, also known as chronic jet lag (CJL), on the lung circadian clock and consequently the immune response to inflammation. We address important questions: How do interactions between clock genes affect the strength of the inflammatory response at CT0 compared to CT12?
Does the disruptive effect of shift work manifest itself differently in males and females? If so, what are the clock genes responsible for the sex-specific responses? Existing mathematical models of the circadian clock that focus on immunity can be classified into two categories: 1) models of the interplay between circadian rhythms and the immune system via neuroendocrine players (e.g. melatonin, cortisol) [18–20]; 2) models for the NF-κB network modulated by the circadian clock [21].
The former do not model the core clock machinery, but rather use rhythmic hormones such as cortisol to drive the circadian variations in the system. The latter include the core clock system but with unidirectional coupling from the clock to the immune system. It is now known that the immune system can affect the circadian clock in a reciprocal manner [15, 22].
Given this observation, we have developed a model of the core circadian clock genes and proteins and their reciprocal interactions with the immune system under acute inflammation. Our mathematical model was extended to include the effect of shift work, represented as an 8h-advance of the circadian phase with sex-specific alterations in the expression of clock genes and proteins (see Fig 1).
Schematic diagram of the acute immune response model (orange shapes) and the circadian clock (blue shapes) in the lung of a rat. In the circadian clock model, slanted boxes denote mRNAs; blue rectangles denote proteins; ovals denote protein complexes. Dotted arrows represent transactivation; blunt dashed arrows represent inhibition. In the acute inflammation model, P denotes endotoxin; D, damage marker; N, activated phagocytic cells; CA, slow-acting anti-inflammatory cytokines.
https://doi.org/10.1371/journal.pcbi.1008514.g001
The immune system is under control of the circadian clock. A primary means of circadian control over the immune system is through direct interactions of clock proteins with components of key inflammatory pathways such as members of the NF-κB protein family [22]. This regulation is independent of transcription and allows the immune system to also reciprocally exert control over the function of the circadian clock [22].
Our model, which is composed of core clock genes (Bmal1, Per, Cry, Rev-Erb and Ror) and their related proteins as well as the regulatory mechanism of pro- and anti-inflammatory mediators (e.g. IL-6, TNF-α and IL-10), predicts temporal profiles of clock gene expression and cytokine expression during inflammation. This allows us to study how immune parameters respond to shift work-mediated circadian disruption. Moreover, we compare how the disruptive effect of shift work manifests itself differently in males and females.
reference link: https://journals.plos.org/ploscompbiol/article?id=10.1371/journal.pcbi.1008514
More information: Stéphanie M. C. Abo et al. Modeling the circadian regulation of the immune system: Sexually dimorphic effects of shift work, PLOS Computational Biology (2021). DOI: 10.1371/journal.pcbi.1008514
