TLR7 promotes skin inflammation via activating NFκB-mTORC1 axis in rosacea.

Rosacea is a chronic inflammatory skin disease originated from damaged skin barrier and innate/adaptive immune dysregulation. Toll-like receptors (TLRs) sense injured skin and initiate downstream inflammatory and immune responses, whose role in rosacea is not fully understood. Here, via RNA-sequencing analysis, we found that the TLR signaling pathway is the top-ranked signaling pathway enriched in rosacea skin lesions, in which TLR7 is highlighted and positively correlated with the inflammation severity of disease. In LL37-induced rosacea-like mouse models, silencing TLR7 prevented the development of rosacea-like skin inflammation. Specifically, we demonstrated that overexpressing TLR7 in keratinocytes stimulates rapamycin-sensitive mTOR complex 1 (mTORC1) pathway via NFκB signaling. Ultimately, TLR7/NFκ B/mTORC1 axis promotes the production of cytokines and chemokines, leading to the migration of CD4+T cells, which are infiltrated in the lesional skin of rosacea. Our report reveals the crucial role of TLR7 in rosacea pathogenesis and indicatesa promising candidate for rosacea treatments.

Whole genome sequencing identifies genetic variants associated with neurogenic inflammation in rosacea.

Rosacea is a chronic inflammatory skin disorder with high incidence rate. Although genetic predisposition to rosacea is suggested by existing evidence, the genetic basis remains largely unknown. Here we present the integrated results of whole genome sequencing (WGS) in 3 large rosacea families and whole exome sequencing (WES) in 49 additional validation families. We identify single rare deleterious variants of LRRC4, SH3PXD2A and SLC26A8 in large families, respectively. The relevance of SH3PXD2A, SLC26A8 and LRR family genes in rosacea predisposition is underscored by presence of additional variants in independent families. Gene ontology analysis suggests that these genes encode proteins taking part in neural synaptic processes and cell adhesion. In vitro functional analysis shows that mutations in LRRC4, SH3PXD2A and SLC26A8 induce the production of vasoactive neuropeptides in human neural cells. In a mouse model recapitulating a recurrent Lrrc4 mutation from human patients, we find rosacea-like skin inflammation, underpinned by excessive vasoactive intestinal peptide (VIP) release by peripheral neurons. These findings strongly support familial inheritance and neurogenic inflammation in rosacea development and provide mechanistic insight into the etiopathogenesis of the condition.

Paroxetine is an effective treatment for refractory erythema of rosacea: Primary results from the Prospective Rosacea Refractory Erythema Randomized Clinical Trial.

BACKGROUND: Patients with refractory erythema of rosacea have limited treatment options. OBJECTIVE: To evaluate the efficacy and safety of a 12-week course of paroxetine for moderate-to-severe erythema of rosacea. METHODS: In a multicenter, randomized, double-blinded, placebo-controlled trial, patients with refractory erythema of rosacea were randomly assigned (1:1) to receive paroxetine 25 mg daily or placebo for 12 weeks. RESULTS: Overall, 97 patients completed the study (paroxetine: 49; placebo: 48). The primary end point was the proportion of participants achieving Clinical Erythema Assessment success (defined as Clinical Erythema Assessment score of 0, 1, or ≥2-grade improvement from baseline) at week 12; this was significantly greater in the paroxetine group than in the placebo group (42.9% vs 20.8%, P = .02). Some secondary end points were met, such as flushing success with point reductions ≥2 (44.9% vs 25.0%, P = .04) and improvement in overall flushing (2.49 ± 3.03 vs 1.68 ± 2.27, P = .047), burning sensation (46.9% vs 18.8%, P = .003), and depression (P = .041). The most reported adverse events associated with paroxetine were dizziness, lethargy, nausea, dyspepsia, and muscle tremors. LIMITATIONS: Only a single-dosage regimen of paroxetine within a 12-week study was evaluated. CONCLUSIONS: Paroxetine is an effective and well-tolerated alternative treatment for moderate-to-severe erythema of rosacea.

SARS-CoV-2 vaccination in androgen sensitive phenotypes - A study on associated factors for SARS-CoV-2 vaccination and its adverse effects among androgenetic alopecia and benign prostate hyperplasia patients.

Background: Androgen sensitivity, which was established as the leading etiology of androgenetic alopecia (AGA) and benign prostatic hyperplasia (BPH), plays an important role in SARS-CoV-2 infection. Vaccination is essential for AGA and BPH patients in view of the high risk from SARS-CoV-2 infection. Purpose: We aimed to investigate the associated factors for SARS-CoV-2 vaccination and its side effects in populations with AGA and BPH. Method: We collected the data on SARS-CoV-2 vaccination and adverse reactions of male AGA and BPH patients visited the outpatient of Xiangya hospital by telephone and web-based questionnaires. Vaccination rate and adverse reactions were compared by different vaccine types and use of anti-androgen therapy. Result: A total of 457 AGA patients and 397 BPH patients were recruited in this study. Among which, 92.8% AGA patients and 61.0% BPH patients had at least the first dose of SARS-CoV-2 vaccination (p < 0.001). Having comorbidities and use of anti-androgen therapy increased the risk of un-vaccination among AGA by 2.875 and 3.729 times, respectively (p < 0.001). Around 31.1% AGA patients and 9.5% BPH patients presented adverse reactions, which were mostly mild. Anti-androgen therapy increased the inclination of injection site pain after vaccination (18.7% vs 11.9%; OR: 1.708, 95% CI: 1.088-2.683, p = 0.019). Conclusion: Co-existence of other systemic diseases and anti-androgen therapy were the limiting factors for SARS-CoV-2 unvaccination, especially in AGA patients. The importance of SARS-CoV-2 vaccines should be strengthened and popularized in androgen sensitive phenotypes.

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.

A Novel Convolutional Neural Network for the Diagnosis and Classification of Rosacea: Usability Study.

BACKGROUND: Rosacea is a chronic inflammatory disease with variable clinical presentations, including transient flushing, fixed erythema, papules, pustules, and phymatous changes on the central face. Owing to the diversity in the clinical manifestations of rosacea, the lack of objective biochemical examinations, and nonspecificity in histopathological findings, accurate identification of rosacea is a big challenge. Artificial intelligence has emerged as a potential tool in the identification and evaluation of some skin diseases such as melanoma, basal cell carcinoma, and psoriasis. OBJECTIVE: The objective of our study was to utilize a convolutional neural network (CNN) to differentiate the clinical photos of patients with rosacea (taken from 3 different angles) from those of patients with other skin diseases such as acne, seborrheic dermatitis, and eczema that could be easily confused with rosacea. METHODS: In this study, 24,736 photos comprising of 18,647 photos of patients with rosacea and 6089 photos of patients with other skin diseases such as acne, facial seborrheic dermatitis, and eczema were included and analyzed by our CNN model based on ResNet-50. RESULTS: The CNN in our study achieved an overall accuracy and precision of 0.914 and 0.898, with an area under the receiver operating characteristic curve of 0.972 for the detection of rosacea. The accuracy of classifying 3 subtypes of rosacea, that is, erythematotelangiectatic rosacea, papulopustular rosacea, and phymatous rosacea was 83.9%, 74.3%, and 80.0%, respectively. Moreover, the accuracy and precision of our CNN to distinguish rosacea from acne reached 0.931 and 0.893, respectively. For the differentiation between rosacea, seborrheic dermatitis, and eczema, the overall accuracy of our CNN was 0.757 and the precision was 0.667. Finally, by comparing the CNN diagnosis with the diagnoses by dermatologists of different expertise levels, we found that our CNN system is capable of identifying rosacea with a performance superior to that of resident doctors or attending physicians and comparable to that of experienced dermatologists. CONCLUSIONS: The findings of our study showed that by assessing clinical images, the CNN system in our study could identify rosacea with accuracy and precision comparable to that of an experienced dermatologist.

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 the incidence of rosacea and drinking or smoking in China. / ä¸­å›½äººç¾¤çŽ«ç‘°ç—¤ç–®å‘ç— ä¸Žé¥®é ’ã€å¸çƒŸçš„å ³ç³».

OBJECTIVES: To explore the relationship between the incidence of rosacea and drinking, smoking, gender or age, and to provide some basis for the diagnosis, treatment and mechanism of rosacea. METHODS: A total of 1 180 patients with rosacea and 1 008 non-rosacea patients diagnosed in the Department of Dermatology of Xiangya Hospital were included in the study. Logistic analysis was performed on the incidence factors, and the differences between the two groups in different age groups were compared. RESULTS: There was no significant difference in gender between the two groups (P>0.05). Logistic analysis showed that drinking had no effect on the incidence of rosacea (P>0.05); while smoking, gender, and age had an effect on the incidence of rosacea (P<0.05). The highest proportion of patients with rosacea was 25-34 years old. CONCLUSIONS: The incidence of rosacea has nothing to do with alcohol consumption; while smoking, gender, and age affect the incidence. Smoking and women are the risk factors, and the most common age of rosacea is at 25-34 years old.

Identification and verification of EOMEs regulated network in Alopecia areata.

Alopecia areata (AA) is a common alopecia characterized by non-scarring hair loss with the dysregulated immunity. However, the pathogenesis of AA remains to be elucidated. In this study, we identified gene signatures and then analyzed transcription factor-immune regulatory network in AA using integrated bioinformatics methods. Finally, we verified potential target genes in lesions of AA patients using qPCR and immunohistochemistry. Here, 74 differentially expressed genes (DEGs) were identified in AA, which were enriched in immune-related signaling pathway. The immune analysis revealed the infiltration of γδT cells and Macrophages M1 in AA lesion. Next, the expression correlation analysis and ChIP-seq results revealed a transcription factor (EOMEs) regulated network. We found that EOMEs, a T-box transcription factor, may be involved in the immunoregulation in AA via targeting CD8A and BMP2, and it may affect keratinocytes function via regulating GZMK, LYPD6, RNF182, KRTAP5-9 and KRT73 expression. Finally, the mRNA expression of these network genes in AA lesions was confirmed using qPCR. And the increase expression of EOMEs was identified at inflammatory cells at the periphery of hair follicles and partial keratinocytes in AA tissue using immunohistochemistry. In conclusions, our research demonstrated that EOMEs may play a key role in the progression of AA via regulating immune cell infiltration and keratinocytes function, indicating EOMEs as a promising therapeutic target of AA.

Epidemiological features of rosacea in Changsha, China: A population-based, cross-sectional study.

Rosacea is a common chronic skin disorder of unknown etiology. While population prevalence rates range 0.2-22% in Europe and North America, prevalence in China is currently undetermined. We conducted a large population-based case-control study to determine the present epidemiological status of rosacea in China, involving 10 095 participants aged 0-100 years (mean age, 35.5 ± 19.1; 50.5% female). A census of rosacea among 15 communities in Changsha in south central China was conducted with skin examination by board-certified dermatologists. Rosacea was observed in 3.48% (95% confidence interval, 3.13-3.85%) of the study population. Subtype distribution was erythematotelangiectatic in 47.6%, papulopustular in 35.0% and phymatous in 17.4%. Family history was noted in 37.8% and ocular symptoms in 31.3%. Associations with rosacea were observed for melasma, hypertension, hyperthyroidism and breast cancer in females (P < 0.05), and also for hyperthyroidism and peptic ulcers in males (P < 0.05). Our results provide baseline information about epidemiological aspects of rosacea in China.

Hydroxychloroquine is a novel therapeutic approach for rosacea.

Rosacea is a chronic inflammatory disease in face. Hydroxychloroquine (HCQ), an anti-malaria drug, was reported to have anti-inflammation activities. However, the role of HCQ on rosacea remains unclear. In this study, we revealed the potential molecular mechanism by which HCQ improved rosacea in rosacea-like mice and mast cells (MCs). Moreover, the effects of HCQ treatment for rosacea patients were investigated. In this study, we found HCQ ameliorated the rosacea-like phenotype and MCs infiltration. The elevated pro-inflammatory factors and mast cell protease were significantly inhibited by HCQ treatment in rosacea-like mice. In vitro, HCQ suppresses LL37-induced MCs activation in vitro, including the release of inflammatory factors, chemotaxis, degranulation and calcium influx. Moreover, HCQ attenuated LL37-mediated MCs activation partly via inhibiting KCa3.1-mediated calcium signaling. Thus, these evidences suggest HCQ ameliorated rosacea-like dermatitis may be by regulating immune response of MCs. Finally, the 8-week HCQ treatment exerted satisfactory therapeutic effects on erythema and inflammatory lesions of rosacea patients, indicating that it is a promising drug for rosacea in clinical treatment.

Induction of melasma by 1064-nm Q-switched neodymium:yttrium-aluminum-garnet laser therapy for acquired bilateral nevus of Ota-like macules (Hori nevus): A study on related factors in the Chinese population.

Laser treatment has emerged as a common treatment modality for acquired bilateral nevus of Ota-like macules (ABNOM). To identify the ratio of melasma induction and exacerbation before and after laser therapy for ABNOM and to observe the risk factors related to the induction and exacerbation of melasma by laser therapy, we analyzed related factors of 1268 adult Chinese patients who underwent 1064-nm Q-switched neodymium:yttrium-aluminum-garnet (Nd:YAG) laser (QNYL) treatment using case series and case-control studies. Overall, 24.0% of the ABNOM patients had mixed melasma. Among the ABNOM patients without melasma, after laser therapy the development of melasma was more frequently noted in patients older than 35 years (P < 0.0001), as well in patients whose ABNOM was less than 10 cm(2) (P = 0.027), ABNOM were light (similar to yellow-brown) in color (P = 0.021) and skin types were closer to type IV (P < 0.0001). New melasma lesions also appeared most frequently in the zygomatic region (P < 0.0001). Among the ABNOM patients with melasma, 89.5% experienced worsening of their melasma, irrespective of their related factors above. We concluded that the risk of inducing melasma is great after 1064-nm QNYL treatment in ABNOM patients, and particularly in the patients with both ABNOM and melasma. ABNOM patients should be treated as early as possible and before the age of 35 years.

Protective role of AQP3 in UVA-induced NHSFs apoptosis via Bcl2 up-regulation.

Aquaporin-3 (AQP3), a water/glycerol-transporting protein that facilitates water, urea, and glycerol transport, can inhibit arsenite-induced apoptosis by up-regulating Bcl-2. However, whether it has a protective role in ultraviolet A (UVA)-induced apoptosis in normal human skin fibroblasts is not known. In this study, we demonstrate that mild UVA treatment fails to induce oxidative cell stress and apoptosis in normal human skin fibroblasts (NHSFs) overexpressing AQP3. After severe UVA irradiation, there was an increase in oxidative cell stress and apoptosis when AQP3 levels decreased. We also found that silencing AQP3 sensitized NHSFs to low-dose UVA. Overexpressing AQP3 was protective against high-dose UVA-induced oxidative stress and apoptosis. Besides, we observed that Bcl-2 may be involved in UVA-induced apoptosis. Our findings suggested that the water/glycerol-transporting protein AQP3 plays a role in resistance to UVA-induced apoptosis.

[In vitro study on the differentiation of bone marrow mesenchymal stem cells into epidermal stem cells].

OBJECTIVE: To explore the feasibility of the differentiation of bone marrow mesenchymal stem cells into epidermal stem cells. METHODS: Human bone mesenchymal stem cells (BMSCs) were isolated from the bone marrow of volunteers' ilium, and were purified and cultured in vitro and induced by supernatant liquid of HaCat cells. The morphologic changes of BMSCs were observed with electron microscope, and immunohistochemical examination was carried out to detect the positive staining of cytokeratin 10, cytokeratin 19 and integrin beta1 after one week induction. RESULTS: Large numbers of flat-polygon cells were closely connected and developed like road metal. The plenty threadlike keratins were observed in the cytoplasm. The immunohistochemical examination showed the positive staining of few cytokeratin 10, a great deal of cytokeratin 19 and integrin beta1 after the one week induction. CONCLUSION: Human BMSCs can differentiate into epidermal stem cells with supernatant liquid of HaCat cells and EGFs in vitro.