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Rosacea is a chronic inflammatory skin disorder, whose underlying cellular and molecular mechanisms remain obscure. Here, we generate a single-cell atlas of facial skin from female rosacea patients and healthy individuals. Among keratinocytes, a subpopulation characterized by IFNγ-mediated barrier function damage is found to be unique to rosacea lesions. Blocking IFNγ signaling alleviates rosacea-like phenotypes and skin barrier damage in mice. The papulopustular rosacea is featured by expansion of pro-inflammatory fibroblasts, Schwann, endothelial and macrophage/dendritic cells. The frequencies of type 1/17 and skin-resident memory T cells are increased, and vascular mural cells are characterized by activation of inflammatory pathways and impaired muscle contraction function in rosacea. Most importantly, fibroblasts are identified as the leading cell type producing pro-inflammatory and vasodilative signals in rosacea. Depletion of fibroblasts or knockdown of PTGDS, a gene specifically upregulated in fibroblasts, blocks rosacea development in mice. Our study provides a comprehensive understanding of the aberrant alterations of skin-resident cell populations and identifies fibroblasts as a key determinant in rosacea development., (© 2024. The Author(s).)

Rosacea is a chronic skin inflammatory disease with a global prevalence ranging from 1% to 20%. It is characterized by facial erythema, telangiectasia, papules, pustules, and ocular manifestations. Its pathogenesis involves a complex interplay of genetic, environmental, immune, microbial, and neurovascular factors. Recent studies have advanced our understanding of its molecular basis, focusing on toll-like receptor (TLR) 2 pathways, LL37 expression, mammalian target of rapamycin (mTOR) activation, interleukin (IL)-17 signaling, transient receptor potential vanilloid (TRPV) functions, and the Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathways. LL37-associated signaling pathways, particularly involving TLR2 and mTORC1, are critical in the pathogenesis of rosacea. LL37 interacts with signaling molecules such as extracellular signal-regulated kinases 1 and 2 (ERK1/2), nuclear factor kappa B (NF- κ B), inflammasomes, C-X-C motif chemokine ligand 8 (CXCL8), mas-related G-protein-coupled receptor X2 (MRGPRX2)-TRPV4, and vascular endothelial growth factor (VEGF). This interaction activates macrophages, neutrophils, mast cells, and vascular endothelial cells, leading to cytokine release including tumor necrosis factor-alpha (TNF- α ), IL-6, IL-1 β , C motif chemokine ligand (CCL) 5, CXCL9, and CXCL10. These processes contribute to immune response modulation, inflammation, and angiogenesis in rosacea pathophysiology. The IL-17 signaling pathway also plays a crucial role in rosacea, affecting angiogenesis and the production of inflammatory cytokines. In addition, recent insights into the JAK/STAT pathways have revealed their integral role in inflammatory and angiogenic mechanisms associated with rosacea. Rosacea treatment currently focuses on symptom management, with emerging insights into these molecular pathways providing more targeted and effective therapies. Biological agents targeting specific cytokines, IL-17 inhibitors, JAK inhibitors, and VEGF antagonists are promising for future rosacea therapy, aiming for enhanced efficacy and fewer side effects. This review provides a comprehensive overview of the current knowledge regarding signaling pathways in rosacea and potential targeted therapeutic strategies., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Yang, Wang, Song, Zhang, Wang, Du and Jiang.)

Rosacea is a chronic inflammatory skin disorder characterized by immune response-dependent erythema and pustules. S100A9, a proinflammatory alarmin, has been associated with various inflammation-related diseases. However, the specific role of S100A9 in rosacea remains unexplored. Therefore, our objective was to unravel the role of S100A9 in the pathogenesis of rosacea and its underlying molecular mechanisms. In this study, we show that expression levels of S100A9 were elevated in both the lesions and serum of patients with papulopustular rosacea as well as in lesions of the LL37-induced rosacea-like mouse model. Moreover, the upregulation of S100A9 was correlated with clinical severity and levels of inflammatory cytokines. In addition, we demonstrated that S100A9 promoted the production of proinflammatory factors in HaCaT cells by activating toll-like receptor 4/MyD88/NF-κB signaling pathways. Notably, inhibition of S100A9 suppressed the progression of rosacea-like dermatitis and inflammatory responses in the LL37-induced rosacea-like mouse model through toll-like receptor 4/MyD88/NF-κB signaling pathways. In conclusion, this study illustrated that S100A9 participates in the pathogenesis of rosacea by upregulating toll-like receptor 4/MyD88/NF-κB signaling pathways, thereby promoting rosacea-associated skin inflammation. These results not only expand our understanding of the potential role of S100A9 in the development of rosacea but also offer greater insight toward targeted therapies., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Rosacea patients show facial hypersensitivity to stimulus factors (such as heat and capsaicin); however, the underlying mechanism of this hyperresponsiveness remains poorly defined. Here, we show capsaicin stimulation in mice induces exacerbated rosacea-like dermatitis but has no apparent effect on normal skin. Nociceptor ablation substantially reduces the hyperresponsiveness of rosacea-like dermatitis. Subsequently, we find that γδ T cells express Ramp1, the receptor of the neuropeptide CGRP, and are in close contact with these nociceptors in the skin. γδ T cells are significantly increased in rosacea skin lesions and can be further recruited and activated by neuron-secreted CGRP. Rosacea-like dermatitis is reduced in T cell receptor δ-deficient (Tcrd -/- ) mice, and the nociceptor-mediated aggravation of rosacea-like dermatitis is also reduced in these mice. In vitro experiments show that CGRP induces IL17A secretion from γδ T cells by regulating inflammation-related and metabolism-related pathways. Finally, rimegepant, a CGRP receptor antagonist, shows efficacy in the treatment of rosacea-like dermatitis. In conclusion, our findings demonstrate a neuron-CGRP-γδT cell axis that contributes to the hyperresponsiveness of rosacea, thereby showing that targeting CGRP is a potentially effective therapeutic strategy for rosacea., (© 2024. The Author(s).)

Background: Recent studies increasingly suggest that microbial infections and the immune responses they elicit play significant roles in the pathogenesis of chronic inflammatory skin diseases. This study uses Mendelian randomization (MR) and Bayesian weighted Mendelian randomization (BWMR) to explore the causal relationships between immune antibody responses and four common skin diseases: psoriasis, atopic dermatitis (AD), rosacea, and vitiligo., Methods: We utilized summary statistics from genome-wide association studies (GWAS) for antibody responses to 13 infectious pathogens and four skin diseases. Single nucleotide polymorphisms (SNPs) were selected as instrumental variables (IVs) to assess causal relationships using multiple MR methods, including inverse variance weighted (IVW), MR Egger, and weighted median. BWMR was also employed to confirm findings and address potential pleiotropy., Results: The IVW analysis identified significant associations between specific antibody responses and the skin diseases studied. Key findings include protective associations of anti-Epstein-Barr virus (EBV) IgG seropositivity and Helicobacter pylori UREA antibody levels with psoriasis and AD. anti-chlamydia trachomatis IgG seropositivity, anti-polyomavirus 2 IgG seropositivity, and varicella zoster virus glycoprotein E and I antibody levels were negatively associated with rosacea, while EBV Elevated levels of the early antigen (EA-D) antibody levels and HHV-6 IE1B antibody levels were positively associated with rosacea. H. pylori Catalase antibody levels were protectively associated with vitiligo, whereas anti-herpes simplex virus 2 (HSV-2) IgG seropositivity was positively associated with vitiligo. The BWMR analysis confirmed these associations., Conclusion: This study underscores the significant role of H. pylori and other pathogens in these skin diseases, suggesting both protective and exacerbating effects depending on the specific condition. Understanding these pathogen-immune interactions can lead to the development of more effective, personalized treatments and preventative strategies, ultimately improving patient outcomes and quality of life., (© 2024 The Author(s). Skin Research and Technology published by John Wiley & Sons Ltd.)

Rosacea is a complex inflammatory condition characterized by papulopustular lesions and erythema on the central face for which there is no cure. The development of rosacea is influenced by both external triggers and genetics, but the common pathophysiology is overactivation of the immune system. Here, we review the current data on proinflammatory cytokines and dysregulation of the neurovascular system as targetable components of rosacea. Amelioration of cutaneous and gastrointestinal dysbiosis and other external factors impacts the immune state and has been observed to improve rosacea. While multiple treatments exist, many patients do not achieve their goals for rosacea control and highlights an unmet need for dermatologic care. Current interventions encompass topical/oral drugs, light devices, and avoidance of triggers management. Additional understanding of the underlying pathogenesis may help us develop novel targeted therapeutic strategies to improve rosacea., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. AC has been an investigator for an investigator initiated rosacea study funded by Novartis., (Copyright © 2024 Tu, Jung, Shih and Chang.)

The pathogenesis of granulomatous rosacea (GR), the only variant of rosacea, is unclear. To investigate the differences between GR and non-granulomatous rosacea (NGR) in clinical characteristics, histopathological changes and gene expression for the purpose of providing new ideas on the pathogenesis of rosacea. A total of 30 GR and 60 NGR patients were included. Their clinical and histopathological information was collected retrospectively, and the characteristics of immune cell infiltration were investigated by multiple immunohistochemical staining. RNA sequencing and transcriptome analysis were performed on three pairs of skin samples from GR and NGR patients, respectively. Then, the expressions of candidate genes that were potentially associated with granuloma formation were verified by immunohistochemical staining. It was found that GR patients were more prone to the occurrence of rosacea in the forehead, periocular and perioral skin (p = 0.001, p < 0.001, p = 0.001), and presented more severe papules and pustules when compared with NGR patients (p = 0.032). For histopathological features, the inflammatory cells primarily infiltrated around hair follicles in the GR group and around blood vessels in the NGR group. In addition, the neutrophils were richer (p = 0.036) and the expression levels of CD4 + , CD8 + and CD68 + cells were higher (p = 0.047, p < 0.001, p < 0.001) in the GR group than in the NGR group. In addition, the GR group had apparent collagen hyperplasia (p = 0.026). A total of 420 differentially expressed genes (DEGs) were detected, and bioinformatics analysis showed that the DEGs were enriched in neutrophil activation, adaptive immune response and other biological processes. Lastly, the candidate genes related to neutrophil activation and collagen hyperplasia, i.e., Cathepsin S (CTSS), Cathepsin Z (CTSZ) and matrix metalloproteinases 9 (MMP9), were confirmed to be highly expressed in the GR group. The clinical and histopathological features of GR exhibited a very diverse pattern compared with NGR, and the underlying mechanisms may be related to neutrophil activation and collagen hyperplasia., (© 2023 Japanese Dermatological Association.)

MAS related G-protein coupled receptor X2 (MRGPRX2) is a G-protein coupled receptor (GPCR) expressed in human mast cells that has been implicated to play an important role in causing pseudo-allergic reactions as well as exacerbating inflammation during asthma and other allergic diseases. Lactic acid, a byproduct of glucose metabolism, is abundantly present in inflamed tissues and has been shown to regulate functions of several immune cells. Because the endogenous ligands for MRGPRX2 (substance P and LL-37) are elevated during pathologic conditions, such as cancer and asthma, and given that lactic acid levels are also enhanced in these patients, we explored the role of lactic acid in regulating mast cells response via MRGPRX2 and MrgprB2, the mouse orthologue of the human receptor. We found that lactic acid suppressed both the early (Ca 2+ mobilization and degranulation) and late (chemokine/cytokine release) phases of mast cell activation; this data was confirmed in LAD2, human skin and mouse peritoneal mast cells. In LAD2 cells, the reduction in degranulation and chemokine/cytokine production mediated by lactic acid was dependent on pH. In agreement with our in vitro studies, lactic acid also reduced passive systemic anaphylaxis to compound 48/80 (a known MRGPRX2/MrgprB2 ligand) and skin inflammation in a mouse model of rosacea that is dependent on MrgprB2 expression on skin mast cells. Our data thus suggest that lactic acid may serve to inhibit mast cell-mediated inflammation during asthma and reduce immune response during cancer by affecting mast cell activation through MRGPRX2., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: Rosacea, a chronic inflammatory skin disorder etiologically associated with immune cells and the antibacterial peptide cathelicidin LL-37, can be effectively treated by oral carvedilol administration., Objective: To investigate the molecular mechanisms underlying carvedilol efficacy in rosacea treatment., Methods: Skin samples of patients with rosacea were subjected to histopathological (hematoxylin and eosin) and immunohistochemical (CD68, Toll-like receptor 2 (TLR2), kallikrein 5, cathelicidin, TNF-α, and IL-1β) evaluation. An in vivo murine rosacea-like inflammation model was established by LL-37 intradermal injection with or without carvedilol gavage-based pretreatment. Erythema proportion (Image J) and skin redness (L*a*b colorimetry) were quantified. Murine skin samples underwent pathological examination for inflammatory status and immunofluorescence staining. Murine skin and lipopolysaccharide-stimulated RAW 264.7 cells with or without carvedilol pretreatment were evaluated by quantitative reverse transcription-polymerase chain reaction and western blotting. Clinical facial images of patients were obtained using the VISIA skin analysis system before, 4, and 6 months following oral carvedilol administration., Results: Rosacea skin lesions exhibited more pronounced inflammatory cell infiltration than peripheral areas, with profound macrophage infiltration and inflammatory cytokines (TLR2, kallikrein 5, cathelicidin, TNF-α, and IL-1β). In vivo , carvedilol alleviated inflammation in LL-37 mice, down-regulating TLR2, KLK5, and cathelicidin expression. In vitro , carvedilol decreased TLR2 expression in RAW 264.7 cells, further reducing KLK5 secretion and LL-37 expression and ultimately inhibiting rosacea-like inflammatory reactions. Clinical manifestations and facial redness obviously improved during 6-month follow-up with systemic carvedilol administration., Conclusion: Carvedilol is effective against rosacea, with inhibition of macrophage TLR2 expression as a novel anti-inflammatory mechanism., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Zhang, Jiang, Sheng, Liu, Liu, Li, Tao, Hu, Wang, Yang, Xu and Liu.)

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., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Deng, Liu, Chen, Huang, Xiao, Gao, Jian, Ouyang, Xu, Li, Shi, Xie, Zhang and Li.)

Rosacea is a chronic inflammatory dermatosis mainly affecting the cheeks, nose, chin, and forehead. Rosacea is characterized by recurrent episodes of flushing or transient erythema, persistent erythema, phymatous changes, papules, pustules, and telangiectasia. The eyes may also be involved. Due to rosacea affecting the face, it has a profound negative impact on quality of life, self-esteem, and well-being. In addition to general skin care, there are several approved treatment options available for addressing these features, both topical and systemic. For some features, intense pulse light, laser, and surgery are of value. Recent advances in fundamental scientific research have underscored the roles of the innate and adaptive immune systems as well as neurovascular dysregulation underlying the spectrum of clinical features of rosacea. Endogenous and exogenous stimuli may initiate and aggravate several pathways in patients with rosacea. This review covers the new phenotype-based diagnosis and classification system reflecting pathophysiology, and new and emerging treatment options and approaches. We address new topical and systemic formulations, as well as recent evidence on treatment combinations. In addition, ongoing studies investigating novel therapeutic interventions will be summarized.

Background: The pathogenesis of rosacea is incompletely understood. Signaling neuropeptides, including PACAP, a regulator of vasodilation and edema, are upregulated in rosacea skin. Here, we evaluated PACAP38-induced rosacea features and examined whether a 5-HT 1B/1D receptor agonist could reduce these features., Methods: A total of 35 patients with erythematotelangiectatic rosacea received an intravenous infusion of 10 pmol/kg/minute of PACAP38 followed by an intravenous infusion of 4 mg sumatriptan or placebo (saline) on two study days in a double-blind, randomized, placebo-controlled, and cross-over trial., Results: PACAP38 increased facial skin blood flow by 90%, dilated the superficial temporal artery by 56%, and induced prolonged flushing and facial edema. Compared with placebo, sumatriptan reduced PACAP38-induced facial skin blood flow for 50 minutes (P = 0.023), constricted the superficial temporal artery for 80 minutes (P = 0.010), and reduced duration of flushing (P = 0.001) and facial edema (P < 0.001)., Conclusions: We established a clinical experimental model of rosacea features and showed that sumatriptan was able to attenuate PACAP38-induced rosacea flushing and edema. Findings support a key role of PACAP38 in rosacea flushing pathogenesis. It remains unknown whether PACAP38 inhibition can improve rosacea., Trial Register: The trial was registered at ClinicalTrials.govNCT03878784 in March 2019., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Lupus miliaris disseminatus faciei (LMDF) is a chronic inflammatory dermatosis of unknown aetiology, most often seen in young adults. Although many treatments for LMDF exist, treatment guidelines have not been developed, and response to therapy is generally unpredictable. We present the results of transcriptomic analysis of LMDF lesional skin, which revealed a variety of differentially expressed genes linking LMDF to alterations in innate and adaptive T helper 1 immunity. Immunohistochemical analysis was also performed, identifying similar changes in T-cell immune responses. Given evidence for increased tumour necrosis factor (TNF) pathway activity, our patient, who had previously been refractory to multiple treatments, was initiated on TNF inhibitor therapy with excellent response. This characterization of the LMDF immune response may lead to improved treatment of this condition., (© 2021 British Association of Dermatologists.)

Rosacea is a chronic, relapsing inflammatory skin disease featured by abnormal activation of immune responses, vascular dysfunction and prominent permeability barrier alterations. Aspirin, as the first nonsteroidal anti-inflammatory drug (NSAID), is widely used for various inflammatory conditions due to its anti-inflammatory and anti-angiogenic properties. However, its effects on rosacea are unclear. In this study, we demonstrated that aspirin dramatically improved pathological phenotypes in LL37-induced rosacea-like mice. The RNA-sequencing analysis revealed that aspirin alleviated rosacea-like skin dermatitis mainly via modulating immune responses. Mechanically, we showed that aspirin decreased the production of chemokines and cytokines associated with rosacea, and suppressed the Th1- and Th17-polarized immune responses in LL37-induced rosacea-like mice. Besides, aspirin administration decreased the microvessels density and the VEGF expression in rosacea-like skin. We further demonstrated that aspirin inhibited the activation of NF-κB signaling and the release of its downstream pro-inflammatory cytokines. Collectively we showed that aspirin exerts a curative effect on rosacea by attenuating skin inflammation and angiogenesis, suggesting a promising therapeutic candidate for the treatment of rosacea., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Rosacea is a chronic inflammatory disease that affects the face skin. It is clinically classified into the following four subgroups depending on its location and severity: erythematotelangiectatic, papulopustular, phymatous, and ocular. Rosacea is a multifactorial disease triggered by favoring factors, the pathogenesis of which remains imperfectly understood. Recognized mechanisms include the innate immune system, with the implication of Toll-like receptors (TLRs) and cathelicidins; neurovascular deregulation involving vascular endothelial growth factor (VEGF), transient receptor potential (TRP) ion channels, and neuropeptides; and dysfunction of skin sebaceous glands and ocular meibomian glands. Microorganisms, genetic predisposition, corticosteroid treatment, and ultraviolet B (UVB) radiation are favoring factors. In this paper, we review the common and specific molecular mechanisms involved in the pathogenesis of cutaneous and ocular rosacea and discuss laboratory and clinical studies, as well as experimental models., (Copyright © 2021 Molecular Vision.)

Background: Rosacea is a chronic inflammatory skin disease whose psychological consequences severely affect patient's quality of life., Objective: To identify candidate genes of rosacea for potential development of new target therapies., Methods: Gene Expression Omnibus datasets were retrieved to obtain differentially expressed genes (DEGs) between rosacea patients and healthy controls. Gene ontology (GO) analyses were used to identify functions of candidate genes. Related signaling pathways of DEGs were analyzed using Kyoto Encyclopedia of Genes and Genomes (KEGG) and gene set enrichment analysis. Protein-protein interaction (PPI) networks were applied using search tools for the retrieval of interacting genes/proteins and modulations involving PPI networks were evaluated with use of the MCODE app., Results: Samples from 19 rosacea patients and 10 healthy controls of dataset GSE65914 were enrolled. A total of 215 DEGs, 115 GO terms and 6 KEGG pathways were identified. A total of 182 nodes and 456 edges were enriched in PPI networks. Maximal clusters showed 15 central nodes and 96 edges. The toll-like receptor (TLR) signaling pathway was the most significant pathway detected and 5 DEGs were identified as candidate genes which included TLR2, C-C motif chemokine (CCL) 5, C-X-C motif chemokine ligand (CXCL) 9, CXCL10 and CXCL11. The results were verified in rosacea patients with use of real-time polymerase chain reaction and immunohistochemistry. Cell-type enrichment analysis revealed 8 lymphocytes that were enriched in rosacea patients., Conclusions: The results suggest that both innate and adaptive immune responses were involved in the etiology of rosacea. Five DEGs in the TLR signaling pathway may serve as potential therapeutic target genes., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Papulopustular rosacea (PPR) is a chronic inflammatory skin disease with limited treatment options. Although multiple pathways have been described to be upregulated in PPR, a mechanistic understanding of the key drivers and interaction between pathways in PPR pathology is lacking. In this study, we utilized PPR skin biopsy explants to integrate both differentially expressed genes and differentially expressed proteins in paired nonlesional and lesional PPR tissue (n = 5 patients). The results of this study identified 92 differentially expressed genes and 20 differentially expressed proteins between paired PPR lesional and nonlesional explants. MAPK and TNF signaling pathways were the most significantly upregulated pathways in PPR lesional tissue and aligned with differently expressed proteins identified in this study. Both MAPK and TNF signaling pathways highlighted IL-1β as a potential central mediator for PPR pathogenesis. In support of this, stimulation of nonlesional explants with IL-1β resulted in transcriptomic and proteomic profiles similar to those of lesional PPR. In this integrative transcriptomic and quantitative protein analysis, we identified several inflammatory genes, proteins, and pathways, which may be contributing to PPR, as well as highlighted a potential role of IL-1β in driving inflammation in PPR., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Rosacea is a complex, chronic, and recurrent dermatologic condition that adversely affects quality of life and self-esteem. However, clinical relevance and molecular mechanisms underlying NEAT1 influence in rosacea remain unclear., Objective: The present study aims to investigate the dynamics and influences of lncRNAs, miRNAs, and mRNAs in rosacea patients, and to explore the impacts of NEAT1 treatments on miR-196a-5p and S100A9 expression in LL37-treated HaCaT cells., Methods: RNA-sequencing of skin tissues from rosacea patients and integrative analyses facilitated comprehensive exploration of lncRNA, mRNA, and miRNA networks. We identified differentially expressed lncRNAs in paired rosacea afflicted and non-lesioned tissues by hub lncRNAs in the ceRNA network. The role of NEAT1 in LL37-treated HaCaT cells was identified by in vitro experiments., Results: There were 237 lncRNAs, 38 miRNAs, and 1784 mRNAs in lesioned skin compared to non-lesioned skin in six rosacea patients. NEAT1 was upregulated in rosacea skin and in LL37-treated HaCaT cells. Moreover, inflammatory damage was able to be reduced in vitro after knockdown of NEAT1. Finally, NEAT1 was able to directly interact with miR-196a-5p, and downregulating miR-196a-5p was efficient in reversing the influence of NEAT1 siRNA on S100A9., Conclusion: We have completed the first genome-wide lncRNA profiling of paired lesioned and non-lesioned samples from rosacea afflicted patients. The NEAT1/miR-196a-5p/S100A9 axis may have played an important role in the dynamics underlying inflammatory responses of rosacea. NEAT1 may have functioned as a competing endogenous RNA which regulated inflammatory responses in rosacea by sponging miR-196a-5p and upregulating S100A9 expression., Competing Interests: Declaration of Competing Interest The authors have no conflict of interest to declare., (Copyright © 2021 Japanese Society for Investigative Dermatology. Published by Elsevier B.V. All rights reserved.)

Background: Acne vulgaris and rosacea are common inflammatory complications of the skin, both characterized by abnormal infiltration of immune cells. The two diseases can be differentiated based on characteristic profile of the immune cell infiltrates at the periphery of disease lesions. In addition, dysregulated infiltration of immune cells not only occur in the acne lesions but also in non-lesional areas of patients with the disease, thus characterizing the immune infiltration in these sites can further enhance our understanding on the pathogenesis of acne., Methods: Five microarray data-sets (GSE108110, GSE53795, GSE65914, GSE14905 and GSE78097) were downloaded from Gene Expression Omnibus. After removing the batch effects and normalizing the data, we applied the CIBERSORT algorithm combined with signature matrix LM22, to describe 22 types of immune cells' infiltration in acne less than 48 hour (H) old, in comparation with non-lesional skin of acne patients, healthy skin and rosacea (including erythematotelangiectatic rosacea, papulopustular rosacea and phymatous rosacea) and we compared gene expression of Th1 and Th17-related molecules in acne, rosacea and healthy control., Results: Compared with the non-lesional skin of acne patients, healthy individuals and rosacea patients, there is a significant increase in infiltration of neutrophils, monocytes and activated mast cells around the acne lesions, less than 48 H after their development. Contrarily, few naive CD4+ T cells, plasma cells, memory B cells and resting mast cells infiltrate acne sites compared to the aforementioned groups of individuals. Moreover, the infiltration of Regulatory T cells (Tregs) in acne lesions is substantially lower, relative to non-lesional sites of acne patients and skin of healthy individuals. In addition, non-lesional sites of acne patients exhibit lower infiltration of activated memory CD4+ T cells, plasma cells, memory B cells, M0 macrophages, neutrophils, resting mast cells but higher infiltration of Tregs and resting dendritic cells relative to skin of healthy individuals. Intriguingly, we found that among the 3 rosacea subtypes, the immune infiltration profile of papulopustular rosacea is the closest to that of acne lesions. In addition, through gene expression analysis of acne, rosacea and skin tissues of healthy individuals, we found a higher infiltration of Th1 and Th17 cells in acne lesions, relative to non-lesional skin areas of acne patients., Conclusions: Our study provides new insights into the inflammatory pathogenesis of acne, and the difference between acne and rosacea, which helps in differentiating the two diseases. Our findings also guide on appropriate target therapy of the immune cell infiltrates in the two disease conditions., Competing Interests: The authors have declared that no competing interests exist.

The increasingly wide use of next-generation sequencing technologies has revolutionised our knowledge of microbial environments associated with human skin, gastrointestinal tract and blood. The collective set of microorganisms influences metabolic processes, affects immune responses, and so directly or indirectly modulates disease. Rosacea is a skin condition of abnormal inflammation and vascular dysfunction, and its progression is affected by Demodex mites on the skin surface. When looking into the effects influencing development of rosacea, it is not only the skin microbiome change that needs to be considered. Changes in the intestinal microbiome and their circulating metabolites, as well as changes in the blood microbiome also affect the progression of rosacea. Recent research has confirmed the increased presence of bacterial genera like Acidaminococcus and Megasphera in the intestinal microbiome and Rheinheimera and Sphingobium in the blood microbiome of rosacea patients. In this review we discuss our current knowledge of the interactions between the immune system and the skin, gut and blood microbiome, with particular attention to rosacea diagnostic opportunities.

Background: Patients with sensitive skin find topical retinoid use for anti-aging purposes challenging due to irritation. Bakuchiol, a meroterpene from the Psoralea corylifolia seed, has retinol functionality through retinol-like regulation of gene expression., Objective: This research examined the tolerability, efficacy, and barrier effects of a nature-based bakuchiol-containing cleanser and moisturizer in subjects with sensitive skin., Methods: 60 female subjects Fitzpatrick skin types I&ndash;V age 40&ndash;65 years with sensitive mild to moderate photodamaged skin were enrolled in this 4 week study. A sensitive skin panel was constructed: 1/3 eczema/atopic dermatitis, 1/3 rosacea, 1/3 cosmetic intolerance syndrome. Subjects used a nature-based cleanser and moisturizer twice daily and underwent transepidermal water loss (TEWL), corneometry, tolerability assessments, and efficacy assessments at baseline, 5&ndash;10 minutes post-application, and week 4., Results: The skin care products were well tolerated and efficacious (P&lt;0.001) in terms of investigator assessed improvement in visual smoothness, tactile smoothness, clarity, radiance, overall appearance, and global anti-aging. Cheek corneometry measurements demonstrated a statistically significant 16% increase in skin moisture content (P&lt;0.001)., Conclusion: A bakuchiol nature-based anti-aging moisturizer is well tolerated and effective in individuals with sensitive skin.J Drugs Dermatol. 2020;19(12): doi:10.36849/JDD.2020.5522.

Background: Rosacea is a chronic skin condition characterized by primary and secondary manifestations affecting the centrofacial skin. The primary diagnostic phenotypes for rosacea are fixed centrofacial erythema with periodic intensification, and phymatous changes. Major phenotypes, including papules and pustules, flushing, telangiectasia, and ocular manifestations, may occur concomitantly or independently with the diagnostic features. The phenotypes of rosacea patients may evolve between subtypes and may require multiple treatments concurrently to be effectively managed. We report the proceedings of a roundtable discussion among 3 dermatologists experienced in the treatment of rosacea and present examples of rosacea treatment strategies that target multiple rosacea symptoms presenting in individual patients., Methods: Three hypothetical cases describing patients representative of those commonly seen by practicing dermatologists were developed. A roundtable discussion was held to discuss overall and specific strategies for treating rosacea based on the cases., Results/discussion: With few exceptions, the dermatologists recommended combination therapy targeting each manifestation of rosacea for each case. These recommendations are in agreement with the current American Acne and Rosacea Society treatment guidelines for rosacea and are supported by several studies demonstrating beneficial results from combining rosacea treatments., Conclusions: Rosacea is an evolving condition; care should take into account all clinical signs and symptoms of rosacea that are present in an individual patient, understanding that symptoms may change over time, and utilize combination therapy when applicable to target all rosacea symptoms. J Drugs Dermatol. 2020;19(10): 929-934. doi:10.36849/JDD.2020.5367.

Background: While most skin diseases benefit from topical steroids, rosacea symptoms are exacerbated by topical steroids. In the rosacea pathogenesis, abnormal innate immune mechanisms including overexpression of the Toll-like receptor (TLR) have been proposed. However, the links between glucocorticoid metabolism and innate immunity in the epidermis have not been elucidated., Objective: In order to understand the pathology by which rosacea symptoms are exacerbated by steroids and environment stimuli, we examined the molecular links between the innate immune system and glucocorticoid synthesis in epidermis., Methods: We examined the expression of glucocorticoid-synthetic enzymes in rosacea skin. We stimulated epidermal keratinocytes by TLR ligands and examined the regulation of glucocorticoid-synthetic enzymes. We also employed siRNA and adenovirus vectors to knockdown and transduce TLR molecules, respectively., Results: Rosacea epidermis showed high HSD11B1 in the granular layer. Among TLR ligands, TLR3 ligand Poly(I:C) enhanced the expression of multiple glucocorticoid-synthetic enzymes including HSD11B1 and CYP11A1, and increased cortisol in the cultured media. Induction of HSD11B1 by Poly(I:C) was abolished by pretreatment with TLR3 siRNA. Transfection with an adenoviral vector incorporating TLR3 enhanced HSD11B1 and CYP11A1 protein expression by Poly(I:C). In addition, cell staining revealed increased expression of HSD11B1 and CYP11A1 proteins in the group transfected with TLR3 under the same conditions., Conclusion: TLR3-stimulated epidermal keratinocytes and rosacea epidermis enhance the expression of glucocorticoid-synthetic enzymes, which would promote cortisol activation in the epidermis. The innate immunity modulates glucocorticoid-synthetic enzymes expression via the TLR3 pathway in epidermal keratinocytes., Competing Interests: Declaration of Competing Interest The authors have no conflict of interest to declare regarding for this article., (Copyright © 2020 Japanese Society for Investigative Dermatology. Published by Elsevier B.V. All rights reserved.)

Rosacea is a complex facial skin condition associated with abnormal inflammation and vascular dysfunction. Next to the known trigger factors, the role of microbiota in the development and aggravation of rosacea continues to raise interest. Demodex folliculorum mites, Helicobacter pylori, Staphylococcus epidermidis, Chlamydia pneumoniae, and the Demodex-associated bacterium, Bacillus oleronius are microbes that have been linked with rosacea. However, the results of studies which assessed their involvement in the disease have been inconsistent and inconclusive. Microbiological research in many different disciplines exploded in recent years as methods to analyze complex microbial communities at the taxonomic and phylogenetic levels became available. Here, we provide an update on the microorganisms implicated in rosacea and review the potential pathogenic role of microbes in the development of rosacea.

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-β1 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., (© 2020 Japanese Dermatological Association.)

Background: Rosacea is an inflammatory disease with 50% of ocular involvement rate. Primary demodicosis is an eruption caused by Demodex mites, and there is no data about the rate of ocular involvement in primary demodicosis., Aims: In this cross-sectional study, it is aimed to reveal the frequency of Demodex blepharitis in rosacea and primary demodicosis patients., Methods: In total, 58 rosacea, 33 primary demodicosis patients, and 31 healthy volunteers were included in the study. Four samples were obtained from eyelashes with a forceps and from facial skin by standardized skin surface biopsy. A positive result is described as detecting at least one Demodex mite on an eyelash or at five mites in the face. The patients were also examined by an ophthalmologist in terms of ocular involvement., Results: Both rosacea and primary demodicosis patients had significantly more complaints like burning and stinging in the eyes compared to the control patients (P = .001). Primary demodicosis and papulopustular rosacea patients had the highest numbers of eyelash mites, respectively, and significantly a higher rate of blepharitis than the control group., Conclusion: As a result, the Demodex count was significantly higher in the primary demodicosis and rosacea patients than the control group. We think that every Demodex-positive patients should be evaluated for also eyelash mites to prevent a possible chronic blepharitis., (© 2019 Wiley Periodicals, Inc.)

Rosacea is a chronic skin disease characterized by photosensitivity, abnormal dermal vascular behavior, inflammation, and enhanced expression of the antimicrobial peptide LL-37. We observed that dermal endothelial cells in rosacea had an increased expression of VCAM1 and hypothesized that LL-37 could be responsible for this response. The digestion of double-stranded RNA from keratinocytes exposed to UVB blocked the capacity of these cells to induce adhesion molecules on dermal microvascular endothelial cells. However, a synthetic noncoding snoU1RNA was only capable of increasing adhesion molecules on endothelial cells in the presence of LL-37, suggesting that the capacity of UVB exposure to promote both double-stranded RNA and LL-37 was responsible for the endothelial response to keratinocytes. Sequencing of RNA from the endothelial cells uncovered the activation of Gene Ontology (GO) pathways relevant to the human disease, such as type I and II interferon signaling, cell-cell adhesion, leukocyte chemotaxis, and angiogenesis. Functional relevance was demonstrated as double-stranded RNA and LL-37 promoted adhesion and transmigration of monocytes across the endothelial cell monolayers. Gene knockdown of TLR3, RIGI, or IRF1 decreased monocyte adhesion in endothelial cells, confirming the role of the double-stranded RNA recognition pathways. These observations show how the expression of LL-37 can lead to enhanced sensitivity to UVB radiation in rosacea., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: The pathogenesis of rosacea is not fully understood. The innate immune system is impaired in patients with rosacea. This leads to abnormal inflammatory cytokine release. It has been proposed that the molecular mechanism for the role of the ABO antigenic system in human diseases may arise from its relationship with the von Willebrand factor and several pro-inflammatory and adhesion molecules. To our knowledge, the relationship between ABO-Rh groups and rosacea has not been investigated previously., Materials and Methods: One hundred and fourteen patients with rosacea and 258 healthy individuals who had blood group record were included in this study. The results were analyzed statistically., Results: In terms of ABO blood groups, 54 (47.4%) patients had A, 14 (12.3%) patients had B, 7 (6.1%) patients had AB, and 39 (34.2%) patients had O blood groups in the patient group. In the control group, 109 (42.2%) individuals had A, 45 (17.5%) individuals had B, 29 (11.2%) individuals had AB, and 75 (29.1%) individuals had O blood group. There was no significant difference between the groups (P > .05). In terms of Rh groups, 103 (90.4%) patients were Rh (+) and 11 (9.6%) patients were Rh (-). In the control group, 220 (85.3%) individuals were Rh (+) and 38 (14.7%) were Rh (-). There was no significant difference between the groups (P > .05)., Conclusion: We did not find a relationship between blood groups and rosacea. But, we think this is an interesting hypothesis. To clarify this possible relationship, comprehensive and further studies are needed in different races and geographic regions., (© 2019 Wiley Periodicals, Inc.)

Mast cells are inflammatory immune cells that play an essential role in mediating allergic reactions in humans. It is well-known that mast cell activation is critically regulated by intracellular calcium ion (Ca 2+ ) concentrations. MAS-related G-protein coupled receptor-X2 (MRGPRX2) is a G-protein coupled receptor (GPCR) expressed on mast cells that is activated by various ligands, including several FDA approved drugs; consequently, this receptor has been implicated in causing pseudo-allergic reactions in humans. MRGPRX2 activation leads to an increase in intracellular Ca 2+ levels; however, the Ca 2+ mobilizing mechanisms utilized by this receptor are largely unknown. Previous reports showed that store-operated Ca 2+ entry (SOCE) via the calcium sensor, stromal interaction molecule 1 (STIM1), regulates mast cell response induced by the high-affinity IgE receptor (FcεRI). In this study, using complementary pharmacologic and genetic ablation approaches we demonstrate that SOCE through STIM1 promotes MRGPRX2-induced human mast cell response in vitro . Importantly, SOCE also critically modulates MrgprB2 (mouse ortholog of human MRGPRX2) dependent inflammation in in vivo mouse models of pseudo-allergy. Collectively, our data suggests that MRGPRX2/MrgprB2 activation of mast cells is dependent on SOCE via STIM1, and further characterization of the MRGPRX2-SOCE-STIM1 pathway will lead to the identification of novel targets for the treatment of pseudo-allergic reactions in humans., (Copyright © 2020 Occhiuto, Kammala, Yang, Nellutla, Garcia, Gomez and Subramanian.)

Background: Previous studies have documented the cosmetic allergic contact dermatitis due to common cosmetic allergens in standard series and various cosmetic products used in rosacea patients; however, the prevalence of contact sensitization to other cosmetic allergens other than those in standard series is largely unknown., Aims: To assess the prevalence of contact sensitization to a European cosmetic series of allergens (Chemotechnique Diagnostics AB, Malmö, Sweden) in rosacea patients and to compare this with the prevalence observed in general population., Methods: In this prospective monocenter study, 103 patients with rosacea and 104 control subjects were investigated for contact sensitizations via patch testing the cosmetic series including 49 allergens., Results: At least one positive allergic reaction was observed in 62 (60.2%) rosacea patients, and in 25 (24.0%) control subjects. Compared with control subjects, rosacea patients were statistically more likely to have positive patch tests. The most common allergens giving positive results were octyl gallate (10.68%), dodecyl gallate (8.74%), tert-Butylhydroquinone (7.77%), thimerosal (6.80%), euxyl K400 (6.80%), cocamidopropyl betaine (5.83%), and 2,6-Di-tert-butyl-4-cresol (4.85%)., Conclusions: This study shows that rosacea patients show a strikingly high prevalence of contact sensitization to cosmetic allergens. We recommend the additional use of cosmetic series for patch testing, and the careful use of cosmetics in rosacea patients if cosmetic contact sensitivity is suspected., (© 2019 Wiley Periodicals, Inc.)

Background: Facial densities of Demodex mites have been observed to be greater in patients with demodicosis and papulopustular rosacea than in healthy control patients. In patients with erythematotelangiectatic rosacea (ETR), this density has been observed to be similar to or greater than that of healthy controls. Erythema and telangiectasia, characteristics of ETR, are often observed among patients with pityriasis folliculorum, a discreet demodicosis, suggesting a possible link between these conditions., Objectives: To compare the facial Demodex densities of patients with clinical ETR and patients with healthy skin, demodicosis, rosacea with papulopustules, and other facial dermatoses., Methods: In this retrospective study, we recorded Demodex densities measured using two consecutive standardized skin surface biopsies (SSSB1 and SSSB2) in 23 patients with ETR, 20 healthy control patients, 590 patients with demodicosis, 254 with rosacea with papulopustules and 180 with other facial dermatoses., Results: Patients with ETR had higher Demodex densities (D cm -2 ) than did the healthy controls (mean ± SEM; SSSB1: 15·7 ± 6·3 vs. 1·8 ± 1·1 D cm -2 , P = 0·042; SSSB2: 38·0 ± 13·7 vs. 5·1 ± 2·1 D cm -2 , P = 0·026) and patients with other dermatoses (SSSB1: 0·4 ± 0·1 D cm -2 , P = 0·004; SSSB2: 1·3 ± 0·3 D cm -2 , P = 0·004), but lower densities than patients with demodicosis (SSSB1: 82·7 ± 4·2 D cm -2 , P = 0·008; SSSB2: 172·2 ± 7·7 D cm -2 , P = 0·001) or rosacea with papulopustules (SSSB1: 86·6 ± 7·3 D cm -2 , P = 0·027; SSSB2: 197·0 ± 12·1 D cm -2 , P = 0·002)., Conclusions: ETR may be associated with nonvisible Demodex proliferation, possibly corresponding to a subclinical stage of demodicosis. Dermatologists should be aware of this potential association and look for subclinical demodicosis in patients with ETR, so that topical acaricidal treatment can be offered if Demodex density is high., (© 2019 British Association of Dermatologists.)

Aims: Our aim was to investigate the skin-homing T-cell immune responses triggered in patients with Demodex infestation and/or rosacea., Methods: Collected whole blood samples were divided into four groups: control subjects; nonrosacea patients with Demodex infestation (Demodex group); papulopustular rosacea (PPR) patients without Demodex infestation (Rosacea group); and PPR patients with Demodex infestation (Rosacea/Demodex group). Following ex vivo activation, skin-homing CLA+CD4+ T-cell subset levels were monitored by flow cytometry., Results: When compared with control subjects, among skin-homing CD4+ T-cell subsets analysed, Demodex patients had higher T H 9 and T reg cell levels; Rosacea subjects displayed elevated T H 1 cell levels; and Rosacea/Demodex patients exhibited increased frequencies of T H 9 and T H 22 cells. In contrast to Rosacea subjects, Rosacea/Demodex group members displayed higher T H 2 cell levels; and when compared with Demodex groups, they had higher T H 1 and T H 2 but lower T reg cell levels. Demodex group members also exhibited higher T reg but lower T H 1 and T H 22 levels than Rosacea/Demodex group subjects., Conclusions: The skin-homing T-cell responses associated with Demodex infestation and rosacea formation seem to influence each other. The present as well as future studies could contribute to the development of effective treatment strategies for demodicosis and rosacea., (© 2019 John Wiley & Sons Ltd.)

Background: Rosacea is a chronic inflammatory skin disorder of uncertain etiology. Evidence suggests the underlying pathogenesis is modulated by abnormal inflammatory and vascular responses. Thalidomide is a synthetic derivative acid with anti-inflammatory and anti-angiogenic properties. However, its effects on rosacea remain unknown., Objectives: To investigate the effects of thalidomide on the lesional alterations and molecular mechanisms in rosacea., Methods: Mice were intradermally injected with LL37 to induce rosacea-like features and intraperitoneally administered with thalidomide. The severity of skin inflammation was evaluated. The mRNA levels of cytokines and chemokines associated with rosacea were assessed by qPCR. The number of CD4 positive infiltrated T helper cells and CD31 positive microvessels, and related-genes were measured by immunofluorescence, qPCR and ELISA. Moreover, the effect of thalidomide on inhibiting NF-κB activation was determined by immunofluorescence and western blot., Results: Our results showed that thalidomide significantly alleviated erythema and reduced inflammatory cell infiltration in dermis of LL37-induced rosacea-like mice. The production of cytokines and chemokines induced by LL37 was decreased by thalidomide in mice skin and HaCaT keratinocytes. Particularly, we showed thalidomide reduced CD4 + T helper cell infiltration and downregulated Th1- and Th17-polarizing genes. In addition, thalidomide treatment lowered the microvessel density and vascular endothelial growth factor (VEGF) expression. We further demonstrated that thalidomide suppressed NF-κB activation in LL37-treated skin and in TNF-α-stimulated HaCaT keratinocytes in vitro., Conclusions: Our findings suggest thalidomide attenuates the inflammation and represses NF-κB activation in skin, which leads to assumptions that thalidomide may be a new therapeutic agent for rosacea., (Copyright © 2019 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Rosacea is common inflammatory facial dermatosis. Rosacea has variable manifestations including facial flushing, central facial erythema, telangiectasias, and papulopustular lesions. Treatment of rosacea is challenging given the varied manifestations and incompletely understood etiology, but the treatment of papulopustular presentations often relies on oral antibiotics. Tetracyclines, specifically doxycycline, are the most commonly prescribed antibiotics for rosacea. Other antibiotics that can be used include macrolides, commonly azithromycin, and rarely, metronidazole. This paper will review the evidence for the use of antibiotics in the treatment of rosacea. J Drugs Dermatol. 2019;18(6):506-513.

The aim of the work was to study the features of the pathogenesis of various clinical forms of rosacea (the presence of mite Demodex folliculorum, the determination of VEGF, IL-2 IL-6, IL-8) and, based on the obtained results, to ensure adequate methods of therapy. Mite identification was performed by microscopy. The concentration of cytokines in patients with various clinical forms of rosacea (papulopustular form 15 patients, steroid form - 15, erythematous telangiectic form - 10, Ophthalmo Rosacea - 3, rhinophyma - 3) was determined by enzyme immunoassay using appropriate monoclonal antibodies and expressed in samples. Based on the results we obtained in the local treatment of patients with papulopustular rosacea (with a high population density of demodicosis ticks and an increased concentration of IL-8 in the blood), 1% ivermectin cream was applied externally to the skin of the face 1 time per day every day for the entire course of treatment (3-4 months). In patients with erythematous-teloangiectatic form (with a high cytokine VEGF, IL-8), a combined phased use of 1% pimecrolimus cream 14 days and 0.5% bromonidine tartrate gel was administered once a day - 14 days (with a single course of 1 month). In patients with a steroid form of rosacea with a high concentration of cytokines (IL-2, IL-6, IL-8), 1% pimecrolimus was administered 2 times a day - 1 month, 1% ivermectin 1 time a day - 14 days. During therapy, patients with advanced treatment were divided into 2 groups. Patients of group 1, who received externally 1% ivermectin 1 time per day as the main therapy, in the evening for 16 weeks. Group 2 applied 1% ivermectin and 1% pimercolimus cream for 16 weeks. In group 2 patients showed a significant improvement in a shorter time (4 weeks compared to 8 weeks in 1 group of patients). Taking into account the torpid flow and the difficulty of rosacea therapy, the pathogenetic approach when choosing new external preparations, opens promising directions for further deeper study of the pathophysiological mechanisms underlying the individual clinical forms of dermatosis. At the same time, the efficacy and safety of using ivermectin, pimecrolimus, and brimonidine tartrate in the treatment of various forms of this dermatosis suggests their widespread use in practical dermatology.

Rosacea is a chronic inflammatory cutaneous disease characterized by immune system anomalies and vascular hyperreactivity. Recently, therapy of rosacea has improved substantially with the approval of Tranexamic acid (TXA), an antifibrinolytic agent. However, we know little about the underlying mechanism. In this study, we evaluated the effects of TXA and its molecular mechanism on rosacea by using LL37-induced mouse model and HaCaT cell model. Rosacea-like symptoms including skin erythema and histopathological alterations, as well as the elevated pro-inflammatory cytokines (IL-6 and TNFα) and MMP9 expression were significantly ameliorated by TXA treatment. In addition, TXA reduced the expression levels of innate immune gene (TLR2, KLK5 and Camp) and neutrophils relative gene in rosacea-like lesion. For adaptive immune, CD4 + T cell infiltration and the gene expression of Th cytokines and chemokines were regulated by TXA in skin lesion. Furthermore, the anti-inflammatory effects of TXA were associated with the inhibition of TLR2, pro-inflammatory cytokines (IL-6 and TNFα) and chemokines (CCL10) expression in LL37-activated HaCaT cells. Finally, TXA repressed the angiogenesis by reducing the number of CD31 + cell and downregulating the expression levels of VEGF in rosacea. In conclusion, our finding defines a treatment mechanism by which TXA ameliorates rosacea symptoms by regulating the immune response and angiogenesis., (Copyright © 2018. Published by Elsevier B.V.)

Background: Rosacea is a frequently seen chronic disease. Certain allergens, some foods and beverages are known to trigger symptoms of rosacea., Objective: We aimed to assess if nickel sensitivity is more common in rosacea patients than the normal population., Method: Fourty patients with rosacea and 40 healthy age and sex-matched volunteers were included in the study. From European standard patch test series, test units with nickel were applied on the skin of the upper back. According to the scheme of the International Contact Dermatitis Research Group (ICDRG), test results were evaluated at 48th, 72th and 96th hours. Seven days later, reevaluation was done for late reactions. Statistical analyses were done by using Statistics package for Social Sciences (SPSS) 17 package program and p<0.05 was accepted as statistically significant., Results: Female/male ratio was 34/6 in patient group and 32/8 in control group. Mean age of the patient group and the control group were 39.97±12.65 (18-65 years), 40.82±11.79 (19-68 years), respectively. Age and sex distributions were found to be statistically similar. Nickel allergy in the patient and control group was found to be 52.5%, 22.5% respectively and the difference between groups was statistically significant (p=0. 006)., Conclusion: Our results showed that there may be an association between nickel sensitivity and rosacea. Nickel sensitivity may be one of the underlying pathology or a triggering factor of the rosacea. Nickel restricted diet and avoiding the use of nickel-containing jewellery and piercings may extend the remission periods., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Background: Rosacea is a chronic inflammatory skin condition whose etiology has been linked to mast cells and the antimicrobial peptide cathelicidin LL-37. Individuals with refractory disease have demonstrated clinical benefit with periodic injections of onabotulinum toxin, but the mechanism of action is unknown., Objectives: To investigate the molecular mechanism by which botulinum toxin improves rosacea lesions., Methods: Primary human and murine mast cells were pretreated with onabotulinum toxin A or B or control. Mast cell degranulation was evaluated by β-hexosaminidase activity. Expression of botulinum toxin receptor Sv2 was measured by qPCR. The presence of SNAP-25 and VAMP2 was established by immunofluorescence. In vivo rosacea model was established by intradermally injecting LL-37 with or without onabotulinum toxin A pretreatment. Mast cell degranulation was assessed in vivo by histologic counts. Rosacea biomarkers were analyzed by qPCR of mouse skin sections., Results: Onabotulinum toxin A and B inhibited compound 48/80-induced degranulation of both human and murine mast cells. Expression of Sv2 was established in mouse mast cells. Onabotulinum toxin A and B increased cleaved SNAP-25 and decreased VAMP2 staining in mast cells respectively. In mice, injection of onabotulinum toxin A significantly reduced LL-37-induced skin erythema, mast cell degranulation, and mRNA expression of rosacea biomarkers., Conclusions: These findings suggest that onabotulinum toxin reduces rosacea-associated skin inflammation by directly inhibiting mast cell degranulation. Periodic applications of onabotulinum toxin may be an effective therapy for refractory rosacea and deserves further study., (Copyright © 2019 Japanese Society for Investigative Dermatology. Published by Elsevier B.V. All rights reserved.)

Papulopustular rosacea and demodicosis are characterized by non-specific symptoms, which can make clinical diagnosis difficult. This retrospective study of 844 patients assessed the diagnostic importance of clinical signs and symptoms that are poorly recognized as being associated with these conditions. In addition to well-known signs (vascular signs (present in 80% of patients), papules (39%), pustules (22%) and ocular involvement (21%)), other signs and symptoms (discreet follicular scales (93%), scalp symptoms (pruritus, dandruff or folliculitis; 38%) and pruritus (15%)) may also suggest a diagnosis not only of demodicosis, but also of papulopustular rosacea. Facial Demodex densities (measured by 2 consecutive standardized skin biopsies) were higher when ocular or scalp involvement was present, suggesting more advanced disease, but further investigations are needed to confirm this hypothesis. Recognition of these clinical signs and symptoms should encourage dermatologists to perform a Demodex density test, thus enabling appropriate diagnosis to be made.

The relationships of demodex density with systemic oxidative stress, inflammatory response, and clinical severity in rosacea are not clear. This study aimed to (a) analyze the levels of systemic oxidative stress, antioxidant capacity, inflammatory parameters, and matrix metalloproteinases (MMPs) in systemic circulation in patients with rosacea, (b) identify the relationship between mite density and both oxidative stress and inflammation, and (c) investigate the role of photoaging and sebum secretion in etiopathogenesis. Forty patients with rosacea and 40 age-, sex-, and skin phenotype-matched healthy volunteers were included in the study. Clinical disease severity of the patients was determined. Sebum levels were measured in both the groups, and photoaging was evaluated. Reflectance confocal microscopy was used to calculate demodex density. Serum total antioxidant capacity (TAC), total oxidant capacity (TOC), myeloperoxidase (MPO), MMP-1, MMP-9, arylesterase (ARES), interleukin-1β (IL-1β), paraoxonase-1 (PON-1), and tumor necrosis factor-α (TNF-α) levels were also analyzed. The patients with rosacea had significantly higher serum TOC and lower TAC levels (p < 0.001). The serum ARES and PON-1 levels were significantly lower (p = 0.045 and p < 0.001, respectively); however, the serum levels of MMP-1, MMP-9, IL-1β and MPO were higher in the patient group. Demodex parameters were higher in the patient group compared to the control group. There was no significant correlation between the number of mites and disease severity. In addition, the number of mites was not correlated with the serum levels of TAC, TOC, OSI, MPO, MMP-1, MMP-9, ARES, PON-1, TNF-α, and IL-1β. However, sebum levels were directly proportional to the number of mites. Photoaging severity was similar between the patients and control subjects. The changing sebaceous microenvironment in rosacea leads to an increase in the number of demodex mites. However, increased demodex density does not alter disease severity, level of oxidative stress, or inflammation. Although none of the patients with rosacea had any underlying systemic disease, patients' systemic oxidative stress and inflammation parameters were found high in systemic circulation. It is assumed that the patients with rosacea are more prone to systemic diseases.

Background: Rosacea is a common facial skin disorder mainly affecting middle-aged adults. Its aetiology is unknown and pathogenesis uncertain. Activation of the host innate immune response has been identified as an important factor. The Demodex mite population in the skin of rosacea patients is significantly higher than in patients with normal skin, suggesting that they may be of aetiological importance in this disorder., Objectives: To determine the potential of Demodex mites to interact with the host immune system., Methods: Live Demodex mites were extracted from normal facial skin of control subjects and used in cell stimulation experiments with the immortalized SZ95 sebocyte line. Time- and mite-dose-dependent experiments were performed. Direct effects of Demodex and effects of the medium in which Demodex had been cultured were evaluated on the Toll-like receptor (TLR) signalling pathway on both a gene and protein expression level., Results: Mites modulated TLR signalling events on both mRNA and protein levels in SZ95 sebocytes. An initial trend towards downmodulation of genes in this pathway was observed. A subsequent switch to positive gene upregulation was recorded after 48 h of coculture. Demodex secreted bioactive molecules that affected TLR2 receptor expression by sebocytes. High numbers of Demodex induced proinflammatory cytokine secretion, whereas lower numbers did not., Conclusions: Demodex mites have the capacity to modulate the TLR signalling pathway of an immortalized human sebocyte line. Mites have the capacity to secrete bioactive molecules that affect the immune reactivity of sebocytes. Increasing mite numbers influenced interleukin-8 secretion by these cells., (© 2018 British Association of Dermatologists.)

A potential role for bacteria in the induction of rosacea has been suggested. The aim of this work was to characterise the effect of temperature on the production of immunostimulatory proteins by Bacillus oleronius-a bacterium to which rosacea patients show sera reactivity and which was originally isolated from a Demodex mite from a rosacea patient. The affected skin of rosacea patients is at a higher temperature than unaffected skin, and it was postulated that this might alter the protein expression pattern of B. oleronius. B. oleronius growth was reduced at 37°C compared to 30°C but resulted in increased expression of the immune-reactive 62kDa protein (1.65 fold [P < 0.05]). Proteomic analysis revealed increased abundance of a wide range of proteins involved in the stress response (e.g. stress proteins [21.7-fold increase], phosphocarrier protein HPr [438.5-fold increase], 60 kDa chaperonin [12.6-fold increase]). Proteins decreased in abundance after growth at 37°C included ferredoxin (325-fold decrease) and peptidase (244-fold decrease). This work indicates that the increased skin temperature of rosacea patients may alter the growth and protein production pattern of B. oleronius and lead to the greater production of immuo-stimulatory proteins.