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

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.

Influence of sleep disruption on inflammatory bowel disease and changes in circadian rhythm genes

“…During nocturnal sleep, the serum levels of IL-6 and IFN γ increase [ 22 ]. Clock proteins regulate the circadian oscillation of the immune system [ 23 , 24 ], and the immune factors produced in turn influence the levels of circadian clock genes and affect sleep quality [ 25 ]. Therefore, it is possible that the inflammatory state and immune factor changes in IBD may be regulated by the circadian clock genes at the early stage.…”

“The ubiquitin ligase SIAH2 is a female-specific regulator of circadian rhythms and metabolism”

“…What these mechanisms are, however, still need to be discovered. Nonetheless, the sex-differences in these circadian mechanisms are essential to recognize and decipher as they may contribute to how males and females cope differently with circadian clock-related disorders [52][53][54][55][56] and possibly other fundamental physiological differences existing between males and females.…”

The Effects of Shift Work on the Immune System: A Narrative Review

“…Female rats produced less pro-inflammatory cytokines compared to male, however the extent depended on time of infection. 40 The authors suggest that the circadian disruption they saw evidence of, is mediated by circadian disruption of REV-ERB and CRY, negatively effecting the expression of IL-6 and IL-10. They also hypothesize the elevated levels of IL-6 and TNFα in males compared to females could leave male rats more vulnerable to sepsis.…”