The circadian clock and diseases of the skin

Abstract

Organisms have an evolutionarily conserved internal rhythm that helps them anticipate and adapt to daily changes in the environment. Synchronized to the light-dark cycle with a period of around 24 hours, the timing of the circadian clock is set by light-triggering signals sent from the retina to the suprachiasmatic nucleus. Other inputs, including food intake, exercise, and temperature, also affect clocks in peripheral tissues, including skin. Here, we review the intricate interplay between the core clock network and fundamental physiological processes in skin such as homeostasis, regeneration, and immune- and stress responses. We illustrate the effect of feeding time on the skin circadian clock and skin functions, a previously overlooked area of research. We then discuss works that relate the circadian clock and its disruption to skin diseases, including skin cancer, sunburn, hair loss, aging, infections, inflammatory skin diseases, and wound healing. Finally, we highlight the promise of circadian medicine for skin disease prevention and management.

Keywords: aging; cancer; circadian clock; circadian medicine; feeding; psoriasis; skin diseases; stem cells; stress and immune response; wound healing.

Figure 1:. The SCN synchronizes peripheral clocks.

Light sends signals through the retina to set the clock in the SCN, which synchronizes peripheral clocks via neuronal and hormonal signals. As indicated, the phase of peripheral clocks is delayed by a few hours compared to the SCN clock. The SCN, however, is not required for the maintenance of peripheral clocks. It is also possible that light-dark cycles directly regulate clocks in the skin. Additionally, other external inputs such as feeding and temperature entrain peripheral clocks, including in the skin.

Figure 2:. A transcription-translation feedback loop generates circadian rhythms.

The core clock has a positive arm, consisting of BMAL1 and CLOCK, and a negative arm, consisting of PER and CRY, which inhibits the BMAL1-CLOCK heterodimer. RORs, REV-ERBS forms a secondary feedback loop to reinforce the oscillatory expression of Bmal1. The clock network directly and indirectly regulates the expression of about 10–20% of genes in each peripheral tissue.

Figure 3:. The skin is a multi-layer, compartmentalized organ.

(A) There are three main layers in the skin: epidermis, dermis and hypodermis. Each layer contains multiple cell types. (B) The interfollicular epidermis contains mostly keratinocytes organized into four layers based on differentiation status. The epidermal stem cells reside in the stratum basale. (C) The anagen hair follicle. The matrix contains proliferating keratinocytes derived from the secondary hair germ, giving rise to the hair shaft. (D) The telogen hair follicle. The hair follicle bulge contains the slow cycling stem cells. The hair germ contains the progenitor cells for the hair. The dermal papilla is a mesenchymal structure that signals to the hair germ and stem cells.

Figure 4:. Food intake regulates skin functions.

Left: Food intake immediately changes the expression of more than 2000 genes in the skin. Heat maps show gene expression before, four hours, and eight hours after food intake. Middle: Time of feeding does not affect the diurnal pattern of cell proliferation in the skin. However, daytime feeding shifts and dampens the expression of circadian genes. Daytime feeding also changes the diurnal variation in sensitivity to UVB-induced DNA damage and the IMQ-induced interferon response. Right: Calorie restriction and high fat diet affect metabolism and expression of rhythmic genes, hair follicle stem cell function, and skin aging. IMQ, imiquimod.