Oxidative Stress and Inflammation Modulate Rev-erbα Signaling in the Neonatal Lung and Affect Circadian Rhythmicity

Aims: The response to oxidative stress and inflammation varies with diurnal rhythms. Nevertheless, it is not known whether circadian genes are regulated by these stimuli. We evaluated whether Rev-erb alpha, a key circadian gene, was regulated by oxidative stress and/or inflammation in vitro and in a mouse model. Results: A unique sequence consisting of overlapping AP-1 and nuclear factor kappa B (NF kappa B) consensus sequences was identified on the mouse Rev-erb alpha promoter. This sequence mediates Rev-erb alpha promoter activity and transcription in response to oxidative stress and inflammation. This region serves as an NrF2 platform both to receive oxidative stress signals and to activate Rev-erb alpha, as well as an NF kappa B-binding site to repress Rev-erb alpha with inflammatory stimuli. The amplitude of the rhythmicity of Rev-erb alpha was altered by pre-exposure to hyperoxia or disruption of NF kappa B in a cell culture model of circadian simulation. Oxidative stress overcame the inhibitory effect of NF kappa B binding on Rev-erb alpha transcription. This was confirmed in neonatal mice exposed to hyperoxia, where hyperoxia-induced lung Rev-erb alpha transcription was further increased with NF kappa B disruption. Interestingly, this effect was not observed in similarly exposed adult mice. Innovation: These data provide novel mechanistic insights into how key circadian genes are regulated by oxidative stress and inflammation in the neonatal lung. Conclusion: Rev-erb alpha transcription and circadian oscillation are susceptible to oxidative stress and inflammation in the neonate. Due to Rev-erb alpha's role in cellular metabolism, this could contribute to lung cellular function and injury from inflammation and oxidative stress.