Dysregulation of Inflammatory Responses by Chronic Circadian Disruption

Abstract

Circadian rhythms modulate nearly every mammalian physiological process. Chronic disruption of circadian timing in shift work or during chronic jet lag in animal models leads to a higher risk of several pathologies. Many of these conditions in both shift workers and experimental models share the common risk factor of inflammation. In this study, we show that experimentally induced circadian disruption altered innate immune responses. Endotoxemic shock induced by LPS was magnified, leading to hypothermia and death after four consecutive weekly 6-h phase advances of the light/dark schedule, with 89% mortality compared with 21% in unshifted control mice. This may be due to a heightened release of proinflammatory cytokines in response to LPS treatment in shifted animals. Isolated peritoneal macrophages harvested from shifted mice exhibited a similarly heightened response to LPS in vitro, indicating that these cells are a target for jet lag. Sleep deprivation and stress are known to alter immune function and are potential mediators of the effects we describe. However, polysomnographic recording in mice exposed to the shifting schedule revealed no sleep loss, and stress measures were not altered in shifted mice. In contrast, we observed altered or abolished rhythms in the expression of clock genes in the central clock, liver, thymus, and peritoneal macrophages in mice after chronic jet lag. We conclude that circadian disruption, but not sleep loss or stress, are associated with jet lag-related dysregulation of the innate immune system. Such immune changes might be a common mechanism for the myriad negative health effects of shift work.

Immunometabolism: Is it under the eye of the clock?

“…However, when treated at midnight, levels of tumour necrosis factor (TNF) ␣ and IL-6 were elevated [54]. Circadian disruption by acute jet-lag caused an exacerbated response to LPS induced death in mice [55]. Mice subjected to 6 hr phase advances of the light/dark schedule over the course of 4 consecutive weeks displayed 81% mortality versus 21% mortality in control mice.…”

“…Altered expression of the core clock genes in the jet-lag mice was evident in the liver, thymus and peritoneal macrophages, however no loss in sleep or altered stress-response was evident. Therefore, circadian disruption, and not sleep loss leads to an increase in the innate immune response following experimentally induced jet-lag in mice [55], which has relevance for the increased inflammatory conditions observed with shift work. Stimulating night shift conditions disrupts the rhythm of immune function in humans [56].…”

Simulated Night Shift Disrupts Circadian Rhythms of Immune Functions in Humans

“…Indeed, studies in rodents and in humans using environmental circadian disruption (e.g., simulated shift work, jetlag, light-dark cycles different from 24 h) associated circadian misalignment with various health consequences (3). For instance, rodents subjected to repeated jetlag exhibit faster tumor growth (4,5) and more severe septic shock in response to endotoxin administration (6). In humans under a 28-h day protocol (forced desynchrony), altered leptin levels, as well as glucose and insulin response after meals (up to a prediabetic level), were observed when the circadian and behavioral cycles were misaligned compared with the days when they were well aligned (7).…”

Blue light reduces organ injury from ischemia and reperfusion

“…The prototypical mediator of central circadian rhythms and photoimmunomodulation is melatonin (29). Nearly every facet of immunity exhibits a circadian pattern and appears under the regulatory influence of melatonin and light (27,28,42,43). Similarly, corticosteroid stress hormones also exhibit circadian rhythm, are modulated by acute light exposure and may influence immunity (15,16).…”