Circadian Control of Pulmonary Endothelial Signaling Occurs via the NADPH Oxidase 2-NLRP3 Pathway

📖 Top 20% JournalSep 15, 2025Journal of biological rhythms

Daily Rhythms Influence Lung Blood Vessel Signaling Through the NADPH Oxidase 2 and NLRP3 Pathway

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Abstract

Disruption of circadian rhythms in pulmonary endothelium was observed following lipopolysaccharide (LPS) treatment.

Circadian rhythms in pulmonary endothelium are regulated by a circadian clock, which plays a role in controlling lung inflammation.
LPS treatment interrupts these rhythms through the generation of reactive oxygen species via (NOX2).
Inhibiting NOX2 prior to LPS exposure successfully restored circadian rhythmicity in the pulmonary endothelium.
In wild-type mice, LPS activates a signaling pathway involving NOX2 and NLRP3, leading to increased inflammation as indicated by higher levels of polymorphonuclear neutrophils and intercellular adhesion molecule-1 on the endothelium.
Clock mutants exhibited a sustained increase in inflammation markers, suggesting that disruption of the circadian clock can lead to chronic inflammatory responses.
Transcriptomic analysis indicates that the aberrant activation of the in clock mutants contributes to their altered inflammatory state.

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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.

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Abstract

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