The pulmonary endothelial circadian clock appears to restrain inflammation through -NLRP3 signaling, while LPS-driven ROS can disrupt endothelial rhythms.
Evidence
This preclinical mouse and isolated-cell study monitored pulmonary endothelial rhythms, LPS responses, NOX2 and NLRP3 inhibition, neutrophil accumulation, ICAM-1 expression, and lung transcriptomic signals.
Caveat
The findings come from mouse tissues, isolated endothelial cells, clock mutants, and LPS challenge, so human lung-disease relevance and natural circadian disruption remain untested.
Simplified
Circadian rhythms are endogenous oscillations that occur with a 24-h periodicity and support organismal homeostasis. While the role of the circadian clock in systemic vasculature is well known, its role in pulmonary vasculature, specifically in the pulmonary endothelium, has remained unexplored. We hypothesized that the circadian clock directly regulates pulmonary endothelium to control lung inflammation. Using pulmonary artery segments and endothelial cells isolated from lungs of mPer2luciferase transgenic mice, we monitored circadian rhythms and observed that lipopolysaccharide (LPS) treatment disrupted rhythmicity. This disruption was mediated by reactive oxygen species (ROS) generated via (NOX2). Remarkably, the pharmacologic inhibition of NOX2 before LPS exposure restored circadian rhythmicity in the pulmonary endothelium. In wild-type (WT) mice, LPS activated a NOX2-NLRP3 signaling axis that drove inflammation as evidenced by increased polymorphonuclear neutrophil (PMN) accumulation and intercellular adhesion molecule-1 (ICAM-1) expression on the pulmonary endothelium. In contrast, disruption of the clock using two different clock mutants (1and) resulted in a sustained baseline elevation of PMN and ICAM-1, which changed minimally with LPS. This effect was attributed to aberrant activation of the at baseline in the clock mutants, as supported by lung transcriptomic data and reversal of the phenotype with an NLRP3 inhibitor. Importantly, these findings also reveal an intriguing bidirectional relationship: while the circadian clock modulates inflammatory responses, inflammatory stimuli in turn alter circadian rhythmicity via the NOX2 pathway. Together, our results identify a novel mechanism by which circadian control of pulmonary endothelial inflammation may be leveraged to mitigate the consequences of clock disruption in lung disease. Bmal Cry1/2 -/--/-
Key numbers
2.05 ± 0.4
Increase in Expression
levels in WT mice after at 24 h.
higher baseline MPO
Increase in Myeloperoxidase (MPO)
Baseline MPO levels in clock mutants vs. WT.
1181
Differentially Expressed Genes
Number of differentially expressed genes between clock mutants and WT.
Full Text
We can’t show the full text here under this license.
