Circadian gene clock regulates psoriasis-like skin inflammation in mice

Abstract

There are several reports suggesting that the pathophysiology of psoriasis may be associated with aberrant circadian rhythms. However, the mechanistic link between psoriasis and the circadian time-keeping system, "the circadian clock," remains unclear. This study determined whether the core circadian gene, Clock, had a regulatory role in the development of psoriasis. For this purpose, we compared the development of psoriasis-like skin inflammation induced by the Toll-like receptor 7 ligand imiquimod (IMQ) between wild-type mice and mice with a loss-of-function mutation of Clock. We also compared the development of IMQ-induced dermatitis between wild-type mice and mice with a loss-of-function mutation of Period2 (Per2), another key circadian gene that inhibits CLOCK activity. We found that Clock mutation ameliorated IMQ-induced dermatitis, whereas the Per2 mutation exaggerated IMQ-induced dermatitis, when compared with wild-type mice associated with decreased or increased IL-23 receptor (IL-23R) expression in γ/δ + T cells, respectively. In addition, CLOCK directly bound to the promoter of IL-23R in γ/δ + T cells, and IL-23R expression in the mouse skin was under circadian control. These findings suggest that Clock is a novel regulator of psoriasis-like skin inflammation in mice via direct modulation of IL-23R expression in γ/δ + T cells, establishing a mechanistic link between psoriasis and the circadian clock.

Diurnal and seasonal variation in psoriasis symptoms

“…The CLOCK gene has been found to regulate mice susceptibility to imiquimod-induced psoriasis-like dermatitis, which is higher in the evening, by modulating the circadian variability of interleukin-23 receptor expression which is important in psoriasis pathophysiology. 8 Furthermore, consistent with Pascoe et al, 2 our study shows clear seasonal patterning, with a trend of psoriasis flaring during winter. There is good evidence that the immune system develops a pro-inflammatory profile during winter, possibly due to evolutionary demands of prepping against infection.…”

Microbial and transcriptional differences elucidate atopic dermatitis heterogeneity across skin sites

“…We speculate that this may have major implications on microbial colonization in AD skin, and consequently on the disease manifestations. Two studies have suggested a connection between epidermal lipid composition and bacterial community composition 44 . Here, linoleic, alpha‐linolenic, and arachidonic acid metabolism were shown to be stimulated in the back and these molecules have been shown to have antimicrobial activity, and may selectively inhibit certain groups of bacteria such as Staphylococcus 45 .…”

“…However, there are studies linking circadian genes to psoriasis-like skin inflammation. 44,54 Furthermore, pruritus and scratching, which are integral parts of the AD, could lead to sleep disruption and in turn may also influence genes which are regulated by circadian rhythm. 55 Further research is required to determine the significance of circadian rhythm genes in the pathogenesis of AD.…”

“…While it has been proposed that circadian rhythm plays a role in AD pathogenesis, the mechanistic evidence for this is still scarce, 53 especially with regard to the relevance of circadian gene expression in the skin. However, there are studies linking circadian genes to psoriasis‐like skin inflammation 44,54 . Furthermore, pruritus and scratching, which are integral parts of the AD, could lead to sleep disruption and in turn may also influence genes which are regulated by circadian rhythm 55 .…”

645 Imiquimod has strain-dependent effects in mice and does not uniquely model human psoriasis

“…Skin adjacent to that collected for RNA was placed into formalin and processed for histology. For all strains, tissues were collected at approximately the same time of day to limit gene expression variation associated with circadian rhythms [26].…”