Abstract
The circadian clock exerts significance influence on the immune system and disruption of circadian rhythms has been linked to inflammatory pathologies. Shift workers often experience circadian misalignment as their irregular work schedules disrupt the natural light-dark cycle, which in turn can cause serious health problems associated with alterations in genetic expressions of clock genes. In particular, shift work is associated with impairment in immune function, and those alterations are sex-specific. The goal of this study is to better understand the mechanisms that explain the weakened immune system in shift workers. To achieve that goal, we have constructed a mathematical model of the mammalian pulmonary circadian clock coupled to an acute inflammation model in the male and female rats. Shift work was simulated by an 8h-phase advance of the circadian system with sex-specific modulation of clock genes. The model reproduces the clock gene expression in the lung and the immune response to various doses of lipopolysaccharide (LPS). Under normal conditions, our model predicts that a host is more sensitive to LPS at circadian time (CT) CT12 versus CT0 due to a dynamic change of Interleukin 10 (IL-10), an anti-inflammatory cytokine. We identify REV-ERB as a key modulator of IL-10 activity throughout the circadian day. The model also predicts a reversal of the times of lowest and highest sensitivity to LPS, with males and females exhibiting an exaggerated response to LPS at CT0, which is countered by a blunted immune response at CT12. Overall, females produce fewer pro-inflammatory cytokines than males, but the extent of sequelae experienced by males and females varies across the circadian day. This model can serve as an essential component in an integrative model that will yield mechanistic understanding of how shift work-mediated circadian disruptions affect the inflammatory and other physiological responses.
Highlights
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]
Shift work relies on irregular work schedules which disrupt the natural sleep-wake cycle
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 [18,19,20]; 2) models for the NF-κB network modulated by the circadian clock [21]
Summary
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]. 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]. Peripheral clocks can be coordinated by systemic cues emanating from the SCN [1], and they can be synchronized by external cues such as temperature, feeding schedules and light [3]. 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]
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