Environmental Circadian Disruption Elevates the IL-6 Response to Lipopolysaccharide in Blood

Abstract

The immune system is regulated by circadian clocks within the brain and immune cells. Environmental circadian disruption (ECD), consisting of a 6-h phase advance of the light:dark cycle once a week for 4 weeks, elevates the inflammatory response to lipopolysaccharide (LPS) both in vivo and in vitro. This indicates that circadian disruption adversely affects immune function; however, it remains unclear how the circadian system regulates this response under ECD conditions. Here, we develop an assay using ex vivo whole-blood LPS challenge to investigate the circadian regulation of immune responses in mice and to determine the effects of ECD on these rhythms. LPS-induced IL-6 release in whole blood was regulated in a circadian manner, peaking during subjective day under both entrained and free-running conditions. This LPS-induced IL-6 release rhythm was associated with daily variation in both white blood cell counts and immune cell responsiveness. ECD increased the overall level of LPS-induced IL-6 release by increasing immune cell responsiveness and not by affecting immune cell number or the circadian regulation of this rhythm. This indicates that ECD produces pathological immune responses by increasing the proinflammatory responses of immune cells. Also, this newly developed whole blood assay can provide a noninvasive longitudinal method to quantify potential health consequences of circadian disruption in humans.

Chrono‐immunology: progress and challenges in understanding links between the circadian and immune systems

“…The intensity of cytokine production upon stimulation appears to sustain rhythmicity in constant darkness, conversely, circadian differences in survival in response to LPS could not be observed under these conditions . It should be noted that the majority of studies investigating diurnal rhythms in susceptibility to infection were consistent regarding the trough in survival rate during the late rest phase despite the use of different protocols ranging from TNF and LPS in BALB/c mice to coxsackie B3 virus infection in CD‐1 mice .…”

Circadian control of pain and neuroinflammation

“…Further, this could lead to potential novel therapeutic options and changes in therapeutic application (e.g., chronotherapy [Bellamy et al, ; Bruguerolle & Labrecque, ; Buttgereit, Smolen, Coogan, & Cajochen, ; Gilron, ; Sunil, Srikanth, Rao, & Murthy, ]). An examination of the contribution of the immune system to inflammatory pain found that a disruption of the circadian cycle (as is possible under disease conditions) causes an increase in the secretion of the proinflammatory cytokines and consequently an enhancement of proinflammatory immune responses (Adams, Castanon‐Cervantes, Evans, & Davidson, ). IL‐6, a cytokine with both pro‐ and anti‐inflammatory actions, has been documented as having a robust circadian rhythm in patients with RA, with elevated levels in the morning (Arvidson et al, ; Perry, Kirwan, Jessop, & Hunt, ).…”

Endocrine Effects of Circadian Disruption

“…Exposure to light at night and to non-24-h light cycles alters inflammatory responses in the peripheral and central nervous systems (113)(114)(115). Environmental circadian disruption is similarly associated with changes in immune response (116)(117)(118). In humans, even acute circadian misalignment reduces circulating cortisol levels and increases inflammatory cytokines (61), and shift work is associated with increased risk for several inflammatory pathologies (119).…”