Regulation of Cutaneous Stress Response Pathways by the Circadian Clock: From Molecular Pathways to Therapeutic Opportunities

Spyk, Elyse van; Greenberg, Milton L.; Mourad, Faraj; Andersen, Bogi

doi:10.1007/978-3-319-43157-4_14

Cited by 3 publications

(2 citation statements)

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“…An important barrier against infections and injury, the epidermis constantly renews through the proliferation of IFE stem cells (1). In these stem cells, the circadian clock controls diurnal rhythms in DNA replication and repair (4,(33)(34)(35); deletion of Bmal1 leads to higher and constant IFE cell proliferation (4). We propose that these daily cell proliferation rhythms allow coordination with diurnal cycles in oxidative phosphorylation and glycolysis to minimize ROS-induced genotoxicity (1,4,5).…”

Section: Discussionmentioning

confidence: 99%

Circadian control of interferon-sensitive gene expression in murine skin

Greenberg

Marshall

Jin

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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The circadian clock coordinates a variety of immune responses with signals from the external environment to promote survival. We investigated the potential reciprocal relationship between the circadian clock and skin inflammation. We treated mice topically with the Toll-like receptor 7 (TLR7) agonist imiquimod (IMQ) to activate IFN-sensitive gene (ISG) pathways and induce psoriasiform inflammation. IMQ transiently altered core clock gene expression, an effect mirrored in human patient psoriatic lesions. In mouse skin 1 d after IMQ treatment, ISGs, including the key ISG transcription factorIFN regulatory factor 7(Irf7),were more highly induced after treatment during the day than the night. Nuclear localization of phosphorylated-IRF7 was most prominently time-of-day dependent in epidermal leukocytes, suggesting that these cell types play an important role in the diurnal ISG response to IMQ. Mice lackingBmal1systemically had exacerbated and arrhythmic ISG/Irf7expression after IMQ. Furthermore, daytime-restricted feeding, which affects the phase of the skin circadian clock, reverses the diurnal rhythm of IMQ-induced ISG expression in the skin. These results suggest a role for the circadian clock, driven by BMAL1, as a negative regulator of the ISG response, and highlight the finding that feeding time can modulate the skin immune response. Since the IFN response is essential for the antiviral and antitumor effects of TLR activation, these findings are consistent with the time-of-day–dependent variability in the ability to fight microbial pathogens and tumor initiation and offer support for the use of chronotherapy for their treatment.

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Section: Discussionmentioning

confidence: 99%

Circadian control of interferon-sensitive gene expression in murine skin

Greenberg

Marshall

Jin

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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“…The likelihood of encountering harmful external stressors is greater during the active phase than during sleep 69 and studies have shown that wounds incurred during the active phase heal faster than wounds incurred during the rest phase. 70 It is, therefore, possible that an increased proportion of IFE stem cells in S-phase during the active phase has evolved to facilitate repair and regeneration in response to wounds and other cellular stressors.…”

Section: Why Does the Circadian Clock Regulate Proliferation Of Ife S...mentioning

confidence: 99%

How and Why the Circadian Clock Regulates Proliferation of Adult Epithelial Stem Cells

2023

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First described in the early 20 th century, diurnal oscillations in stem cell proliferation exist in multiple internal epithelia, including in the gastrointestinal track, and in the epidermis. In the mouse epidermis, 3- to 4-fold more stem cells are in S-phase during the night than during the day. Work that is more recent showed that an intact circadian clock intrinsic to keratinocytes is required for these oscillations in epidermal stem cell proliferation. The circadian clock also regulates DNA excision repair and DNA-damage in epidermal stem cells in response to ultraviolet B radiation. During skin inflammation, epidermal stem cell proliferation is increased and diurnal oscillations are suspended. Here we discuss possible reasons for the evolution of this stem cell phenomenon. We argue that the circadian clock coordinates intermediary metabolism and the cell cycle in epidermal stem cells to minimize accumulation of DNA damage from metabolism-generated reactive oxygen species. Circadian disruption, common in modern society, leads to asynchrony between metabolism and the cell cycle, and we speculate this will lead to oxidative DNA damage, dysfunction of epidermal stem cells, and skin aging.

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