Circadian Clock and OxInflammation: Functional Crosstalk in Cutaneous Homeostasis

Abstract

Circadian rhythms are biological oscillations that occur with an approximately 24 h period and optimize cellular homeostasis and responses to environmental stimuli. A growing collection of data suggests that chronic circadian disruption caused by novel lifestyle risk factors such as shift work, travel across time zones, or irregular sleep-wake cycles has long-term consequences for human health. Among the multiplicity of physiological systems hypothesized to have a role in the onset of pathologies in case of circadian disruption, there are redox-sensitive defensive pathways and inflammatory machinery. Due to its location and barrier physiological role, the skin is a prototypical tissue to study the influence of environmental insults induced OxInflammation disturbance and circadian system alteration. To better investigate the link among outdoor stressors, OxInflammation, and circadian system, we tested the differential responses of keratinocytes clock synchronized or desynchronized, in an in vitro inflammatory model exposed to O 3 . Being both NRF2 and NF-κB two key redox-sensitive transcription factors involved in cellular redox homeostasis and inflammation, we analyzed their activation and expression in challenged keratinocytes by O 3 . Our results suggest that a synchronized circadian clock not only facilitates the protective role of NRF2 in terms of a faster and more efficient defensive response against environmental insults but also moderates the cellular damage resulting from a condition of chronic inflammation. Our results bring new insights on the role of circadian clock in regulating the redoxinflammatory crosstalk influenced by O 3 and possibly can be extrapolated to other pollutants able to affect the oxinflammatory cellular processes.

Dissecting the Crosstalk Between Nrf2 and NF-κB Response Pathways in Drug-Induced Toxicity

“…Interestingly, some researchers have found that synchronized circadian clocks could not only enhance the protective role of Nrf2 but also attenuate the validated response through the NF-κB signaling pathway when testing the differential responses of keratinocytes clock synchronized or desynchronized in challenged keratinocytes by O3. The synchronized circadian clocks can strengthen the cellular defense function and alleviate skin inflammation, which provides new insight into the crosstalk of Nrf2 and NF-κB (Frigato et al, 2020).…”

Pilot Study: Nutritional and Preclinical Safety Investigation of Fermented Hispidin-Enriched Sanghuangporus sanghuang Mycelia: A Promising Functional Food Material to Improve Sleep

“…According to a recent study, sleep deprivation for 5 consecutive days markedly reduced the protein expression level of Nrf2 in the hippocampus of rats ( 34 ). Moreover, loss of Nrf2 function in mouse fibroblasts, hepatocytes and liver can alter circadian gene expression and rhythmicity, which can disrupt normal sleep patterns and impact the timing and length of sleep ( 35 ). According to our previous study, Sanghuangporus sanghuang mycelium can regulate Nrf2-associated pathways and protect liver cells from paracetamol-induced hepatotoxicity by inhibiting oxidative stress ( 36 ).…”

Circadian Deregulation as Possible New Player in Pollution-Induced Tissue Damage

“…Moreover, the role of clock synchronization in protecting human tissues from environmental injury has been properly described. In particular, it has been shown that in clock-entrained human keratinocytes exposed to oxidative stressors, the activation of NRF2, the key master of the antioxidant pathway, is faster and more efficient compared to arrhythmic cells [7,82].…”

“…In particular, several proinflammatory cutaneous conditions (such as psoriasis, eczema, cutaneous rashes, and atopic dermatitis) have been attributed to environmental factors, such as O 3 [80,81]. In a recent study, our group has suggested that a synchronized circadian clock not only facilitates the protective role of the defensive pathway in terms of a faster and more efficient antioxidant response against environmental insults, but also moderates the cellular damage resulting from chronic inflammation [82].…”