Circadian Rhythms in Bacterial Sepsis Pathology: What We Know and What We Should Know

Abstract

Sepsis is a syndrome caused by a deregulated host response to infection, representing the primary cause of death from infection. In animal models, the mortality rate is strongly dependent on the time of sepsis induction, suggesting a main role of the circadian system. In patients undergoing sepsis, deregulated circadian rhythms have also been reported. Here we review data related to the timing of sepsis induction to further understand the different outcomes observed both in patients and in animal models. The magnitude of immune activation as well as the hypothermic response correlated with the time of the worst prognosis. The different outcomes seem to be dependent on the expression of the clock gene Bmal1 in the liver and in myeloid immune cells. The understanding of the role of the circadian system in sepsis pathology could be an important tool to improve patient therapies.

REV-ERBα negatively regulates NLRP6 transcription and reduces the severity of Salmonella infection in mice

“…A fully functioning circadian clock facilitates the mobilization of immune cells, allowing for optimal antimicrobial immune responses. In addition, the circadian clock modulates the expression rhythm of genes involved in antimicrobial responses and their products in cells, which can result in different outcomes depending on the timing of infection [ 43 , 44 ]. REV-ERBα, a nuclear receptor, is an important regulator in various diseases, such as metabolic disorders, inflammatory diseases, and cancers [ 24 ].…”

Circadian rhythm disruption in critically ill patients

“…68 The characteristic "cytokine storm" during systemic inflammatory response (SIRS) and compensatory anti-inflammatory response syndrome (CARS) to a pathogen show increased concentrations of IL-6, IL-1β, IL-10, TNF-α, and others that are well known to be under circadian regulation. 69 In animal models, a distinct daily variation in mortality due to septic shock is observed: mice injected intraperitoneally with high doses of LPS at the end of their resting phase show a higher mortality rate than those injected in the middle phase of activity. 70 Interestingly, the peak in diurnal variation in sepsis severity in mice (end of the resting phase) is contrasting the inflammatory response to pulmonary LPS or bacterial stimuli, peaking at the beginning of the resting phase, 55 suggesting that the pulmonary and systemic clocks are responding differently to the same central rhythm.…”

“…Long‐term psychological, cognitive, and physical disorders are common among survivors and, in face of the severity of this disease pathology, no effective therapy to reduce mortality is known so far 68 . The characteristic “cytokine storm” during systemic inflammatory response (SIRS) and compensatory anti‐inflammatory response syndrome (CARS) to a pathogen show increased concentrations of IL‐6, IL‐1β, IL‐10, TNF‐α, and others that are well known to be under circadian regulation 69 …”

Circadian regulation of innate immunity in animals and humans and implications for human disease

“…This article is a contribution to the special issue on: Chronoimmunology: from preclinical assessments to clinical applications -Guest Editors: Henrik Oster & David Ray information about the sympathetic nervous system, circadian rhythms and inflammation, is a large topic and was reviewed by Leach and Suzuki [56] recently. Lastly, entrainment of the liver clock via feeding cues will NOT be provided, because this is an ongoing topic and has been provided a mini-review very recently here [72].…”