Rosacea is a chronic inflammatory skin disorder whose pathogenesis is unclear. Here, several lines of evidence were provided to demonstrate that mTORC1 signaling is hyperactivated in the skin, especially in the epidermis, of both rosacea patients and a mouse model of rosacea‐like skin inflammation. Both mTORC1 deletion in epithelium and inhibition by its specific inhibitors can block the development of rosacea‐like skin inflammation in LL37‐induced rosacea‐like mouse model. Conversely, hyperactivation of mTORC1 signaling aggravated rosacea‐like features. Mechanistically, mTORC1 regulates cathelicidin through a positive feedback loop, in which cathelicidin LL37 activates mTORC1 signaling by binding to Toll‐like receptor 2 (TLR2) and thus in turn increases the expression of cathelicidin itself in keratinocytes. Moreover, excess cathelicidin LL37 induces both NF‐κB activation and disease‐characteristic cytokine and chemokine production possibly via mTORC1 signaling. Topical application of rapamycin improved clinical symptoms in rosacea patients, suggesting mTORC1 inhibition can serve as a novel therapeutic avenue for rosacea.

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Although patients with rosacea often consult dermatologists for dietary factors that might be related to their skin disorders, few studies have been conducted to research the relationship between rosacea and dietary factors. The purpose of this study was to evaluate the potential relationship between rosacea and diet among the large Chinese population with rosacea, which would provide dietary guidelines for patients with rosacea. A multicenter case–control study was conducted. The feeding frequency 2 years before the occurrence of rosacea was collected by standardized questionnaires. Multiple logistic regression analysis was used to calculate risks related to the diet. One thousand three hundred and forty‐seven patients with rosacea and 1290 controls were enrolled in our study. We found that high‐frequency intake of fatty food and tea presented a positive correlation with rosacea, while high‐frequency dairy product intake showed significant negative correlation with rosacea. Sweet food, coffee and spicy food appeared to be independent of any subset of rosacea in our study. However, high‐frequency dairy product intake showed a borderline beneficial effect on rosacea severity. We further analyzed the correlation between diet and the subtype of rosacea. We found that high‐frequency fatty intake was associated with erythematotelangiectatic rosacea (ETR) and phymatous rosacea, while high‐frequency tea intake was only associated with ETR. In addition, high‐frequency dairy product intake showed negative correlations with ETR and papulopustular rosacea. Rosacea is associated with some dietary factors, and our study is valuable in establishing dietary guidelines to prevent and improve rosacea.

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Rosacea is a chronic inflammatory skin disorder whose pathophysiological mechanism remains largely unknown. Although recent studies have revealed the hypersensitivity of the skin towards chemical, thermal and biological stimuli, there is no direct molecular evidence suggesting the skin barrier is impaired in rosacea. In this study, we demonstrated that the mRNA levels of most claudins (CLDN), the main components of tight junctions determining the major barrier of the paracellular pathway between epithelial cells, were lowered in lesional skin of rosacea patients, especially with erythematotelangiectatic (ETR) and papulopustular (PPR) subtypes. Immunohistochemical analysis showed a significant decrease in the expression of CLDN1, CLDN3, CLDN4 and CLDN5 in the epidermis of ETR and PPR patients. However, the expression of other skin barrier genes, such as filaggrin, loricrin and keratin 10, was not altered. In vitro, various rosacea trigger factors reduced the protein levels of CLDN1, CLDN3 and CLDN5 in keratinocytes. Taken together, our results demonstrate a significant decrease in the expression of CLDN rather than other skin barrier genes, which may be associated with an impaired skin barrier responsible for the development of rosacea.

Skin aging is a complicated physiological process and epigenetic feature, including microRNA-mediated regulation and DNA methylation, have been shown to contribute to this process. DNA methylation is regulated by DNA methyltransferase, of which DNA methyltransferase 1 (DNMT1) is the most abundantly known. But evidence supporting its role in skin aging remains scarce, and no report regards its specifical upstream-regulating molecules in the process of skin aging so far. Here, we found that DNMT1 expression was markedly higher in young human skin fibroblasts (HSFs) than that in passage-aged HSFs, and DNMT1 knockdown significantly induced the senescence phenotype in young HSFs. We predicted the upstream miRNAs which could regulate DNMT1 with miRNA databases and found miR-377 had high homology with a sequence in the 3′-UTR of human DNMT1 mRNA. We confirmed that miR-377 was a potential regulator of DNMT1 by luciferase reporter assays. miR-377 expression in passage-aged HSFs was markedly higher than that in the young HSFs. miR-377 overexpression promoted senescence in young HSFs, and inhibition of miR-377 reduced senescence in passage-aged HSFs. Moreover, these functions were mediated by targeting DNMT1. Microfluidic PCR and next-generation bisulfite sequencing of 24 senescent-associated genes' promoters revealed alterations of the promoter methylation levels of FoxD3, p53, and UTF1 in HSFs treated with miR-377 mimics or inhibitors. We also verified that the miR-377-mediated changes in p53 expression could be reversed by regulation of DNMT1 in HSFs. Similarly, there was a negative correlation between miR-377 and DNMT1 expression in young and photoaged HSFs, HSFs, or skin tissues from UV-unexposed areas of different aged donors. Our results highlight a novel role for miR-377-DNMT1-p53 axis in HSF senescence. These findings shed new light on the mechanisms of skin aging and identify future opportunities for its therapeutic prevention.

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