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

Abstract

In mice, time of day strongly influences lethality in response to LPS, with survival greatest at the beginning compared to the end of the light cycle. Here we show that feeding, rather than light, controls time-of-day dependent LPS sensitivity. Mortality following LPS administration is independent of cytokine production and the clock regulator BMAL1 expressed in myeloid cells. In contrast, deletion of BMAL1 in hepatocytes globally disrupts the transcriptional response to the feeding cycle in the liver and results in constitutively high LPS sensitivity. Using RNAseq and functional validation studies we identify hepatic farnesoid X receptor (FXR) signalling as a BMAL1 and feeding-dependent regulator of LPS susceptibility. These results show that hepatocyte-intrinsic BMAL1 and FXR signalling integrate nutritional cues to regulate survival in response to innate immune stimuli. Understanding hepatic molecular programmes operational in response to these cues could identify novel pathways for targeting to enhance endotoxemia resistance.

The Programmed Cell Death of Macrophages, Endothelial Cells, and Tubular Epithelial Cells in Sepsis-AKI

“…Currently, there is no effective treatment for sepsis-AKI other than supportive care in the form of dialysis. Despite considerable progress in this field (18)(19)(20)(21), there are still no standardized and satisfactory therapeutic strategies for sepsis-AKI.…”

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

“…In response to a sterile injury in the liver, LPMs invaded afflicted tissue via direct recruitment across the mesothelium ( Wang and Kubes, 2016 ). Regarding this, it was recently found that conditional deletion of Bmal1 in hepatocytes (Bmal1 ΔHep ) results in constitutively high LPS sensitivity ( Geiger et al., 2021 ) suggesting that liver signals could induce the arrival of LPMs in a clock-dependent way.…”

“…Therefore, it is not surprising to find that Bmal1 is related to pro-inflammatory and anti-inflammatory processes, which are both deregulated during sepsis. In contrast, daily differences after LPS inoculation were not abolished in Bmal1 ΔMye mice maintained under a time-restricted feeding schedule ( Geiger et al., 2021 ). This discrepancy could be due to the different kinetics observed in the sepsis-induced mortality between models since the survival time was shorter in the last mentioned study.…”

“…This discrepancy could be due to the different kinetics observed in the sepsis-induced mortality between models since the survival time was shorter in the last mentioned study. In addition, it is possible that mice fed only during the night have more robust peripheral circadian rhythms that may compensate for the lack of Bmal1 in myeloid cells, similar to what happens with the rhythm of the respiratory exchange rate in the same work ( Geiger et al., 2021 ).…”

“…Regarding anti-inflammatory mechanisms, the serum levels of IL-10 and corticosterone increased after LPS injection, without time differences ( Mul Fedele et al., 2020 ; Geiger et al., 2021 ). It has been shown that, in animal models, the stimulation of the HPA axis (which is responsible for glucocorticoid secretion) increases resistance to the endotoxic shock ( Dejager et al., 2010 ; Gilibert et al., 2014 ).…”