Susceptibility rhythm to bacterial endotoxin in myeloid clock-knockout mice

Abstract

Local circadian clocks are active in most cells of our body. However, their impact on circadian physiology is still under debate. Mortality by endotoxic (LPS) shock is highly time-of-day dependent and local circadian immune function such as the cytokine burst after LPS challenge has been accounted for the large differences in survival. Here, we investigate the roles of light and myeloid clocks on mortality by endotoxic shock. Strikingly, mice in constant darkness (DD) show a three-fold increased susceptibility to LPS as compared to mice in light-dark conditions. Mortality by endotoxic shock as a function of circadian time is independent of light-dark cycles as well as myeloid CLOCK or BMAL1 as demonstrated in conditional knockout mice. Unexpectedly, despite the lack of a myeloid clock these mice still show rhythmic patterns of pro-and anti-inflammatory cytokines such as TNFα, MCP-1, IL-18 and IL-10 in peripheral blood as well as time-of-day and site dependent traffic of myeloid cells. We speculate that systemic time-cues are sufficient to orchestrate innate immune response to LPS by driving immune functions such as cell trafficking and cytokine expression. 10/15 12/15

Feeding-induced resistance to acute lethal sepsis is dependent on hepatic BMAL1 and FXR signalling

“…3e-h). Although this result contrasts with previous reports of enhanced sensitivity to LPS in myeloid cellspecific BMAL1 deficiency 4,5 , our findings are in a model with earlier onset of symptoms, and are supported by a recent study 25 , which also challenges the notion of enhanced mortality in these conditional knockout mice.…”

The Role of Circadian Clock Genes in Critical Illness: The Potential Role of Translational Clock Gene Therapies for Targeting Inflammation, Mitochondrial Function, and Muscle Mass in Intensive Care

“…Spatiotemporal regulation of the transcriptome of the liver at least has been elegantly illustrated ( Droin et al, 2020 ). The circadian clock helps provide a “metronome” for coordinating metabolism ( Weger et al, 2021 ), hypoxic/oxidative stress ( Cunningham et al, 2020 ; O’Connell et al, 2020 ), and immune function ( Guo et al, 2019 ), to provide the best “setting” for response to external triggers ( Lang et al, 2019 ).…”

“…More recently, the Ray group showed that a mouse model BMAL1 knockout ( Kitchen et al, 2020 ) had improved mortality in Streptococcal pneumonia , secondary to improved macrophage motility and phagocytic function. Since then, a further mouse model has demonstrated that there is a time-of-day-responsive lethality to septic insult ( Lang et al, 2019 ), irrespective of the myeloid clock being present, and mortality increased three times if kept in constant dark. This shows that there is more than one regulatory cue affecting this time-of-day response.…”