Diurnal Variation in Endotoxin-Induced Mortality in Mice: Correlation With Proinflammatory Factors

Abstract

Many immune parameters exhibit daily and circadian oscillations, including the number of circulating cells and levels of cytokines in the blood. Mice also have a differential susceptibility to lipopolysaccharide (LPS or endotoxin)-induced endotoxic shock, depending on the administration time in the 24 h light-dark (LD) cycle. We replicated these results in LD, but we did not find temporal differences in LPS-induced mortality in constant darkness (DD). Animals challenged with LPS showed only transient effects on their wheel locomotor activity rhythm without modification of circadian period and phase. Levels of several key factors involved in the pathology of sepsis and septic shock were tested in LD. We found that LPS-induced levels of interleukin (IL)-1beta, IL-6, JE (MCP-1), and MIP1alpha were significantly higher at zeitgeber time (ZT) 11 (time of increased mortality) than at ZT19 (ZT12 = time of lights-off in the animal quarters for the 12L:12D condition). Our results indicate that the differences found in mortality that are dependent on the time of LPS-challenge are not directly related to an endogenous circadian clock, and that some relevant immune factors in the development of sepsis are highly induced at ZT11, the time of higher LPS-induced mortality, compared to ZT19.

A circadian based inflammatory response – implications for respiratory disease and treatment

“…Similarly, bacterial infection has been shown to lead to higher mortality when initiated during the rest period (Shackelford and Feigin 1973). More recently, these results were confirmed and extended showing that exposing mice to LPS at the end of their rest period or beginning of the active period resulted in a stronger cytokine response and NF-κB activation compared with LPS exposure starting during the active period or beginning of the rest period (Marpegan et al 2009;Gibbs et al 2012;Nguyen et al 2013;Spengler et al 2012). Similar results have been obtained in humans using the LPS challenge both in vivo injecting LPS to healthy volunteers (Alamili et al 2014) and in vitro exposing blood samples obtained at different times of the day from volunteers to LPS (Petrovsky et al 1998;Rahman et al 2015).…”

Circadian Variation of the Response of T Cells to Antigen

“…Given that the DC-OVA immunization approach bypasses events prior to Ag presentation to T cells, the effect we see in vivo is most likely not due to an APC-intrinsic clock. For the same reasons, this day-night difference of response to DC-OVA immunization is probably not explained by the stronger innate responses observed in the rest period (11,12,30,53). Rather, the day-night difference probably relies either on a T cell-intrinsic factor, on the effect of a systemic cue acting on T cells (immunomodulatory hormones, autonomic signals, sleep/wake cycles, spleen environment), or on a combination of rhythmic T cell and rhythmic systemic cue processes.…”

“…In rodents, susceptibility to lethal doses of the bacterial endotoxin LPS presents a diurnal rhythm (11,12) and is exacerbated upon circadian disruption (13). Similarly, mortality following pneumococcal infection varies according to time of day (14).…”

Core circadian protein CLOCK is a positive regulator of NF-κB–mediated transcription

“…Many immune parameters exhibit daily variations, including the number of specific immune cells in circulation and plasma levels of cytokines (1). Consistent with this variation, daily fluctuations in susceptibility to a powerful challenge to the immune system [i.e., to the administration of a bacterial lipopolysaccharide (LPS)] (2) were correlated with daily variation in the induction of proinflammatory cytokines (3). A growing body of evidence shows that peripheral immune cells harbor functional molecular clocks.…”