Keratinocyte-Immune Cell Crosstalk in a STAT1-Mediated Pathway: Novel Insights Into Rosacea Pathogenesis.

Rosacea is a common chronic inflammatory condition that mainly affects the central face. However, the molecular background of the normal central face and the transcriptional profiling and immune cell composition of rosacea lesions remain largely unknown. Here, we performed whole-skin and epidermal RNA-seq of central facial skin from healthy individuals, lesions and matched normal skin from rosacea patients. From whole-skin RNA-seq, the site-specific gene signatures for central facial skin were mainly enriched in epithelial cell differentiation, with upregulation of the activator protein-1 (AP1) transcription factor (TF). We identified the common upregulated inflammatory signatures and diminished keratinization signature for rosacea lesions. Gene ontology, pathway, TF enrichment and immunohistochemistry results suggested that STAT1 was the potential core of the critical TF networks connecting the epithelial-immune crosstalk in rosacea lesions. Epidermal RNA-seq and immunohistochemistry analysis further validated the epithelial-derived STAT1 signature in rosacea lesions. The epidermal STAT1/IRF1 signature was observed across ETR, PPR, and PhR subtypes. Immune cell composition revealed that macrophages were common in all 3 subtypes. Finally, we described subtype-specific gene signatures and immune cell composition correlated with phenotypes. These findings reveal the specific epithelial differentiation in normal central facial skin, and epithelial-immune crosstalk in lesions providing insight into an initial keratinocyte pattern in the pathogenesis of rosacea.

Willingness-to-Pay and Benefit-Cost Analysis of Botulinum Toxin for the Treatment of Rosacea in China: Findings from a Web-Based Survey.

PURPOSE: Botulinum toxin (BTX) is a new treatment approach primarily aimed at relieving flushing and erythema for rosacea, but it is expensive and lacks economic benefit evaluation studies.This study aimed to investigate willingness-to-pay (WTP) of BTX treatment and conduct benefit-cost analysis (BCA) to assess if BTX treatment for rosacea is recommendable from a viewpoint of economics in China. METHODS: WTP of BTX treatment in rosacea and information of sociodemographic and clinical characteristics were inquired via an online questionnaire among the Chinese rosacea patients. The WTP was inquired by photos of three cases with different severities of rosacea before and after BTX treatment. The benefit-cost ratio (BCR) was calculated by dividing WTP by cost. Factors associated with WTP were identified using logistic regression models. RESULTS: The average costs of BTX treatment were USD410.09. The mean WTP for Case 1, Case 2, and Case 3 was USD295.53, 307.91, and 311.78, respectively (p<0.05 for Case 1 vs Case 3). 44.31% to 47.52% of Chinese rosacea patients were willing to pay for the BTX treatment. The BCRs were 0.72, 0.75, and 0.76 for Case 1, Case 2, and Case 3, respectively. A positive correlation between WTP and visiting frequency in the past year (OR=1.181-1.200, p=0.015-0.032, for Cases 1 and 2) or Dermatology Life Quality Index (DLQI) score (OR=2.022-2.266, all p<0.01) was observed, but duration (OR=0.521-0.564, p<0.05, for Cases 1 and 2) of rosacea was negatively correlated with WTP. CONCLUSION: For rosacea patients with poor quality of life, and those with high visiting frequency, BTX should be regarded as a recommendable new treatment in China.

A positive feedback loop between mTORC1 and cathelicidin promotes skin inflammation in rosacea.

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.

Relationship between rosacea and sleep.

Rosacea is a chronic facial skin disease involved in neurovascular dysregulation and neurogenic inflammation. Behavioral factors such as stress, anxiety, depression and sleep were identified to be associated with other inflammatory skin diseases. Few studies have reported sleep status in rosacea. Aiming to investigate the relationship between rosacea and sleep, a case-control survey was conducted, enrolling 608 rosacea patients and 608 sex- and age-matched healthy controls. Sleep quality was assessed through the Pittsburgh Sleep Quality Index (PSQI) questionnaire. Diagnosis and severity grading of rosacea were evaluated under the standard guidelines of the National Rosacea Society. More rosacea patients (52.3%, n = 318) suffered poor sleep quality (PSQI, >5) than the healthy controls (24.0%, n = 146), displaying a much higher PSQI score (rosacea vs control, 6.20 vs 3.95). There was a strong association between sleep quality and rosacea (odds ratio [OR], 3.525; 95% confidence interval [CI], 2.759-4.519). Moreover, the severity of rosacea was also associated with sleep quality (OR, 1.847; 95% CI, 1.332-2.570). Single nucleotide polymorphisms in hydroxytryptamine receptor 2A and adrenoceptor-ß1 genes, which are associated with sleep behaviour, were detected and revealed to be associated with rosacea. Furthermore, the LL-37-induced rosacea-like phenotype and sleep-deprivation mice models were applied, revealing that sleep deprivation aggravated the rosacea-like phenotype in mice, with higher expression of matrix metallopeptidase 9, Toll-like receptor 2, cathelicidin antimicrobial peptide and vascular endothelial growth factor. In conclusion, rosacea patients presented poorer sleep quality, as well as a higher propability of genetic background with sleep disturbance. In addition, poor sleep might aggravate rosacea through regulating inflammatory factors, contributing to a vicious cycle in the progression of disease.