Modeling the circadian regulation of the immune system: Sexually dimorphic effects of shift work

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. Author summary Shift work has a negative impact on health and can lead to chronic diseases and illnesses. Under regular work schedules, rest is a night time activity and work a daytime activity. Shift work relies on irregular work schedules which disrupt the natural sleep-wake cycle. This can in turn disrupt our biological clock, called the circadian clock, a network of molecular interactions generating biochemical oscillations with a near 24-hour period. Clock genes regulate cytokines before and during infection and immune agents can also impact the clock function. We provide a mathematical model of the circadian clock in the rat lung coupled to an acute inflammation model to study how the disruptive effect of shift work manifests itself in males and females during inflammation. Our results show that the extent of sequelae experienced by male and female rats depends on the time of infection. The goal of this study is to provide a mechanistic insight of the dynamics involved in the interplay between these two systems.