Histone and Histone Acetylation-Related Alterations of Gene Expression in Uninvolved Psoriatic Skin and Their Effects on Cell Proliferation, Differentiation, and Immune Responses.

Psoriasis is a chronic immune-mediated skin disease in which the symptom-free, uninvolved skin carries alterations in gene expression, serving as a basis for lesion formation. Histones and histone acetylation-related processes are key regulators of gene expression, controlling cell proliferation and immune responses. Dysregulation of these processes is likely to play an important role in the pathogenesis of psoriasis. To gain a complete overview of these potential alterations, we performed a meta-analysis of a psoriatic uninvolved skin dataset containing differentially expressed transcripts from nearly 300 individuals and screened for histones and histone acetylation-related molecules. We identified altered expression of the replication-dependent histones HIST2H2AA3 and HIST2H4A and the replication-independent histones H2AFY, H2AFZ, and H3F3A/B. Eight histone chaperones were also identified. Among the histone acetyltransferases, ELP3 and KAT5 and members of the ATAC, NSL, and SAGA acetyltransferase complexes are affected in uninvolved skin. Histone deacetylation-related alterations were found to affect eight HDACs and members of the NCOR/SMRT, NURD, SIN3, and SHIP HDAC complexes. In this article, we discuss how histone and histone acetylation-related expression changes may affect proliferation and differentiation, as well as innate, macrophage-mediated, and T cell-mediated pro- and anti-inflammatory responses, which are known to play a central role in the development of psoriasis.

Are the Cutaneous Microbiota a Guardian of the Skin's Physical Barrier? The Intricate Relationship between Skin Microbes and Barrier Integrity.

The skin is a tightly regulated, balanced interface that maintains our integrity through a complex barrier comprising physical or mechanical, chemical, microbiological, and immunological components. The skin's microbiota affect various properties, one of which is the establishment and maintenance of the physical barrier. This is achieved by influencing multiple processes, including keratinocyte differentiation, stratum corneum formation, and regulation of intercellular contacts. In this review, we summarize the potential contribution of Cutibacterium acnes to these events and outline the contribution of bacterially induced barrier defects to the pathogenesis of acne vulgaris. With the combined effects of a Westernized lifestyle, microbial dysbiosis, epithelial barrier defects, and inflammation, the development of acne is very similar to that of several other multifactorial diseases of barrier organs (e.g., inflammatory bowel disease, celiac disease, asthma, atopic dermatitis, and chronic rhinosinusitis). Therefore, the management of acne requires a complex approach, which should be taken into account when designing novel treatments that address not only the inflammatory and microbial components but also the maintenance and strengthening of the cutaneous physical barrier.

Psoriatic Resolved Skin Epidermal Keratinocytes Retain Disease-Residual Transcriptomic and Epigenomic Profiles.

The disease-residual transcriptomic profile (DRTP) within psoriatic healed/resolved skin and epidermal tissue-resident memory T (TRM) cells have been proposed to be crucial for the recurrence of old lesions. However, it is unclear whether epidermal keratinocytes are involved in disease recurrence. There is increasing evidence regarding the importance of epigenetic mechanisms in the pathogenesis of psoriasis. Nonetheless, the epigenetic changes that contribute to the recurrence of psoriasis remain unknown. The aim of this study was to elucidate the role of keratinocytes in psoriasis relapse. The epigenetic marks 5-methylcytosine (5-mC) and 5-hydroxymethylcytosine (5-hmC) were visualized using immunofluorescence staining, and RNA sequencing was performed on paired never-lesional and resolved epidermal and dermal compartments of skin from psoriasis patients. We observed diminished 5-mC and 5-hmC amounts and decreased mRNA expression of the ten-eleven translocation (TET) 3 enzyme in the resolved epidermis. SAMHD1, C10orf99, and AKR1B10: the highly dysregulated genes in resolved epidermis are known to be associated with pathogenesis of psoriasis, and the DRTP was enriched in WNT, TNF, and mTOR signaling pathways. Our results suggest that epigenetic changes detected in epidermal keratinocytes of resolved skin may be responsible for the DRTP in the same regions. Thus, the DRTP of keratinocytes may contribute to site-specific local relapse.

Tumour Necrosis Factor Alpha-induced Protein 3 Negatively Regulates Cutibacterium acnes-induced Innate Immune Events in Epidermal Keratinocytes.

Human epidermal keratinocytes sense the presence of human skin microbiota through pathogen recognition receptors, such as toll-like receptors, and induce innate immune and inflammatory events. In healthy epidermis there is an absence of inflammation despite the continuous presence of cutaneous microbes, which is evidence of an effective immune regulatory mechanism. The aim of this study was to investigate tumour necrosis factor alpha-induced protein 3 (TNFAIP3), a negative regulator of toll-like receptor and nuclear factor kappa B signalling pathways, and its role in these regulatory events. A broad spectrum of toll-like receptor ligands induced TNFAIP3 expression, as did live Cutibacterium acnes, which is involved in the pathogenesis of acne. Changes in bacterium-induced, dose-dependent TNFAIP3 expression were Jun kinase- and nuclear factor kappa B-dependent, and resulted in altered cytokine and chemokine levels in in vitro cultured human keratinocytes. In acne lesions, TNFAIP3 mRNA expression was elevated compared with non-lesional skin samples from the same individuals. These results suggest that TNFAIP3 may have a general role in fine regulation of microbiota-induced cutaneous immune homeostasis.

Targeting the gut-skin axis-Probiotics as new tools for skin disorder management?

The existence of a gut-skin axis is supported by increasing evidence, but its translational potential is not widely recognized. Studies linked inflammatory skin diseases to an imbalanced gut microbiome; hence, the modulation of the gut microbiota to improve skin condition seems to be a feasible approach. Today, there is a growing interest in natural products as alternatives to synthetic drugs. In this respect, oral probiotics could be a simple, safe and cheap modality in the therapeutic management of skin inflammation. Unfortunately, very few studies have looked into how probiotic supplementation influences inflammatory skin disorders. The result, though promising, are difficult to implement in clinical practice due to the heterogeneity of the applied supplemental regimen in the different studies. In this Viewpoint, we aim to encourage the conduction of more research in that direction to explore unambiguously the therapeutic potential of oral probiotics in dermatology. We focus on the most common inflammatory skin diseases (atopic dermatitis, psoriasis, rosacea, acne vulgaris) with an associated gut dysbiosis, but we also discuss some less common, but very serious skin pathologies (eg erythema nodosum, pyoderma gangrenosum, hidradenitis suppurativa) that are possibly linked to a disturbed gut flora composition. We dissect the possible mechanisms along the gut-skin axis and highlight novel points where probiotics could interfere in this communication in the diseased state.

Analysis of psoriasis-relevant gene expression and exon usage alterations after silencing of SR-rich splicing regulators.

In our recent cDNA microarray experiment, three SR-rich splicing factors-SFRS18, PPIG and LUC7L3-were shown to exert altered responsiveness upon T-lymphokine stimulation of psoriatic non-involved and healthy epidermis samples. We have also demonstrated that double silencing LUC7L3 and SFRS18 efficiently decreased production of the psoriasis-associated EDA+ fibronectin isoform. These findings prompted the further investigation of signalling pathways affected by LUC7L3 and SFRS18. To detect gene expression and splicing pattern alterations upon double silencing of LUC7L3 and SFRS18 in an HPV-immortalised keratinocyte cell culture, paired-end RNA sequencing was carried out. Marked changes in exon usage were revealed, in contrast to the modest alterations detected in gene expression, providing a closer delineation of the potential targets of the examined splicing factors. The most prominent gene expression change was detected for IFI6, an interferon-inducible gene highly expressed in psoriasis. Interacting partners of IFI6 and certain psoriasis-associated transcripts also exhibited significantly increased expression upon silencing. In addition to elevated abundance of the EDA+ fibronectin interactor ITGA5, we confirmed decreased EDA domain inclusion, which agrees well with our prior experimental data. Furthermore, differential exon usage was established for the transcription element CREB1, along with HERC6 and CUL1, which are implicated in ubiquitination. Although immortalised keratinocytes express low levels of TINCR, a long non-coding RNA involved in terminal differentiation of keratinocytes, splicing alterations were successfully demonstrated for this RNA as well. We believe that the targeted investigation of mRNA maturation disturbances may help us gain deeper insight into the molecular pathogenesis of psoriasis.

Differential Inflammatory-Response Kinetics of Human Keratinocytes upon Cytosolic RNA- and DNA-Fragment Induction.

Keratinocytes are non-professional immune cells contributing actively to innate immune responses partially by reacting to a wide range of molecular patterns by activating pattern recognition receptors. Cytosolic nucleotide fragments as pathogen- or self-derived trigger factors are activating inflammasomes and inducing anti-viral signal transduction pathways as well as inducing expression of inflammatory cytokines. We aimed to compare the induced inflammatory reactions in three keratinocyte cell types-normal human epidermal keratinocytes, the HaCaT cell line and the HPV-KER cell line-upon exposure to the synthetic RNA and DNA analogues poly(I:C) and poly(dA:dT) to reveal the underlying signaling events. Both agents induced the expression of interleukin-6 and tumor necrosis factor α in all cell types; however, notable kinetic and expression level differences were found. Western blot analysis revealed rapid activation of the nuclear factor κB (NF-κB), mitogen activated protein kinase and signal transducers of activator of transcription (STAT) signal transduction pathways in keratinocytes upon poly(I:C) treatment, while poly(dA:dT) induced slower activation. Inhibition of NF-κB, p38, STAT-1 and STAT-3 signaling resulted in decreased cytokine expression, whereas inhibition of mitogen-activated protein kinase kinase 1/2 (MEK1/2) signaling showed a negative feedback role in both poly(I:C)- and poly(dA:dT)-induced cytokine expression. Based on our in vitro results nucleotide fragments are able to induce inflammatory reactions in keratinocytes, but with different rate and kinetics of cytokine expression, explained by faster activation of signaling routes by poly(I:C) than poly(dA:dT).

Propionic Acid Produced by Propionibacterium acnes Strains Contri-butes to Their Pathogenicity.

Propionibacterium acnes is an important member of the skin microbiome. The bacterium can initiate signalling events and changes in cellular properties in keratinocytes. The aim of this study was to analyse the effect of the bacterium on an immortalized human keratinocyte cell line. The results show that various P. acnes strains affect the cell-growth properties of these cells differentially, inducing cytotoxicity in a strain-specific and dose-dependent manner. We propose that bacterially secreted propionic acid may contribute to the cytotoxic effect. This acid has a role in maintaining skin pH and exhibits antimicrobial properties, but may also have deleterious effects when the local concentration rises due to excessive bacterial growth and metabolism. These results, together with available data from the literature, may provide insight into the dual role of P. acnes in healthy skin and during pathogenic conditions, as well as the key molecules involved in these functions.

Different activations of toll-like receptors and antimicrobial peptides in chronic rhinosinusitis with or without nasal polyposis.

Both up- and down-regulation of the Toll-like receptors (TLRs) and antimicrobial peptides (AMPs) of the sinonasal mucosa have already been associated with the pathogenesis of chronic rhinosinusitis with (CRSwNP) or without (CRSsNP) nasal polyps. The objective of this study was to determine the expression of all known TLR and several AMP genes and some selected proteins in association with allergy, asthma and aspirin intolerance (ASA) in CRS subgroups. RT-PCR was applied to measure the mRNA expressions of 10 TLRs, four defensins, lysozyme, cathelicidin and lactoferrin (LTF) in sinonasal samples from patients with CRSsNP (n = 19), CRSwNP [ASA(-): 17; ASA(+): 7] and in control subjects (n = 12). Protein expressions were detected with immunohistochemistry (n = 10). Statistical analysis was done with the Kruskal-Wallis ANOVA, Mann-Whitney U, and Student t test. TLR2, TLR5, TLR6, TLR7, TLR8, TLR9, ß-defensins 1 and 4, cathelicidin and LTF mRNA expressions were significantly (p < 0.05) increased in CRSwNP, whereas only TLR2 and LTF were up-regulated in CRSsNP compared to controls. There was no statistical difference in respect of allergy, aspirin intolerance and smoking between CRSsNP, ASA(-) and ASA(+) CRSwNP patients. TLR2, TLR3, TLR4, LTF, ß defensin 2 and lysozyme protein expressions were found to be elevated in macrophages of CRSwNP samples (p < 0.05). Gene expression analysis showed markedly different expressions in CRSwNP (6 out of 10 TLR and 4 out of 7 AMP genes were up-regulated) compared to CRSsNP (1/10, 1/7). The distinct activation of the innate immunity may support the concept that CRSsNP and CRSwNP are different subtypes of CRS. These findings were found to be independent from allergy, asthma, smoking, aspirin intolerance and systemic steroid application.

HUNGARIAN EXPERIENCES WITH THE BELIEFS ABOUT ATTRACTIVENESS SCALE.

BACKGROUND AND PURPOSE: Sociocultural influences regarding bodily appearance and their psychological consequences play a considerable role in the development and maintenance of body image disturbance and eating disorders. The purpose of the study was to explore the psychometric properties of the Beliefs About Attractiveness Scale-Revised and its correlates among young adults in Hungary. METHODS: In our cross-sectional online study, participants were 18-35 years old (N = 820, 40% male). MEASURES: self-reported anthropometric data, Beliefs About Attractiveness Scale-Revised, Eating Disorder Inventory, SCOFF questionnaire, Sociocultural Attitudes Towards Appearance Questionnaire-3, and Rosenberg Self-esteem Scale. RESULTS: The exploratory factor analysis showed that the fit indices of the three-factor solution are acceptable (χ²(171)) = 5124.8, p < 0.001, CFI = 0.944, TLI = 0.918, RMSEA = 0.054, SRMR = 0.030). Along the original 'Importance of being thin' and the 'Importance of being fit' factors, a third factor emerged, namely the 'Life fulfilment aspect of attractiveness' factor. Internal consistency and construct validity of the scales were confirmed. Among those who were at risk of developing an eating disorder, all of the measured beliefs were significantly greater than among those who were not at risk (thin: Z = 6.501, p < 0.001, Cohen's d = 0.63, fit: t(818) = -4.749, p < 0.001, Cohen's d = 0.41, and life fulfilment: t(239) = -5.702, p < 0.001, Cohen's d = 0.53). CONCLUSION: The Hungarian version of the Beliefs About Attractiveness Scale-Revised is a reliable, valid measure and we suggest its introduction into Hungarian research. Relationships between beliefs about attractiveness and self- esteem, body image and eating disorders suggest intervention opportunities in with regards to prevention and treatment of eating disorders.

The European Initiative ProYouth for the promotion of mental health and the prevention of eating disorders screening results in Hungary.

OBJECTIVE: The ProYouth programme focuses on the promotion of mental health and the prevention of eating disorders (EDs) among young people. The aim of our study was to explore whether the programme can address individuals who are at risk for developing 2EDs. METHOD: This study is designed as an online cross-sectional survey (n = 664, 12.2% men, 87.8% women, mean age: 24.9 years, SD = 5.4 years, range: 18-40 years). Measures included demographic data, self-reported weight and height, the Patient Health Questionnaire for Depression and Anxiety, Short Evaluation of Eating Disorders, Weight Concerns Scale and previous/current treatment for EDs. RESULTS: In terms of severity of EDs, 22.9% (n = 152) of the screened participants were symptom free, 48.8% (n = 324) had considerable concerns about their weight, 11.1% (n = 74) were slightly impaired, 15.1% (n = 100) had severe impairment and 2.1% (n = 14) of participants are currently under treatment for EDs. In total, 56.3% of users (n = 374) registered in the programme. According to our results, those who had considerable concerns about their weight and individuals who were severely impaired registered with a greater odds to the programme than those who were symptom free [odds ratio (OR) = 1.64, p = .021 and OR = 1.90, p = .023, respectively]. Furthermore, those who previously received treatment for their ED registered to the programme with greater odds than those who did not (OR = 2.40, p = .017). CONCLUSION: ProYouth successfully addressed those who have elevated concerns about their weight and who also registered with greater odds to the programme than those who were symptom free regarding EDs. The screening results show that there is a greater need for specialized care targeting EDs in Hungary than what is currently available.

The -308 G>A SNP of TNFA is a factor predisposing to chronic rhinosinusitis associated with nasal polyposis in aspirin-sensitive Hungarian individuals: conclusions of a genetic study with multiple stratifications.

Single nucleotide polymorphisms (SNPs) of the tumour necrosis factor alpha (TNFα) gene (TNFA) have been extensively studied and shown to be associated with an increased risk of the development of various chronic inflammatory diseases. Inflammation has been demonstrated to play a central role in the pathogenesis of chronic rhinosinusitis (CRS), and TNFα is a key pro-inflammatory cytokine with important functions in these processes. In order to determine whether the well-known TNFA -308 G>A SNP has a role in a genetic predisposition to CRS in the Hungarian population, we analyzed our genomic collection containing control and CRS patient samples in a case-control study, and compared the genotype and allele frequencies. There was no significant difference in the observed genotype or allele frequencies between the controls and the total CRS group. However, after careful stratification of the patient group on the basis of the observed clinical symptoms, we found a significantly higher carriage rate of the rare A allele-containing genotypes among the CRS patients with nasal polyposis (NP) who also exhibited sensitivity to aspirin (acetylsalicylic acid, ASA(+)). It is concluded that genetic variants of the TNFA gene may affect the risk of CRS in a clinically well-defined group of CRSNP(+)ASA(+) patients in the Hungarian population. Our results also emphasize that the group of CRS patients is not homogenous in that patients exhibiting different clinical symptoms exist. Their carried genetic predisposing factors, and as a result, the exact molecular events leading to the development of various forms of CRS, may also differ.

Regulatory networks contributing to psoriasis susceptibility.

The non-involved, healthy-looking skin of psoriatic patients displays inherent characteristics that make it prone to develop typical psoriatic symptoms. Our primary aim was to identify genes and proteins that are differentially regulated in the non-involved psoriatic and the normal epidermis, and to discover regulatory networks responsible for these differences. A cDNA microarray experiment was performed to compare the gene expression profiles of 4 healthy and 4 psoriatic non-involved epidermis samples in response to T-cell lymphokine induction in organotypic cultures. We identified 61 annotated genes and another 11 expressed transcripts that were differentially regulated in the psoriatic tissues. Bioinformatics analysis suggested that the regulation of cell morphology, development and cell death is abnormal, and that the metabolism of small molecules and lipids is differentially regulated in psoriatic epidermis. Our results indicate that one of the early steps of psoriasis pathogenesis may be the abnormal regulation of IL-23A and IL-1B genes in psoriatic keratinocytes.

Na+/Ca2+ exchangers regulate the migration and proliferation of human gastric myofibroblasts.

Gastrointestinal myofibroblasts are contractile, electrically nonexcitable, transitional cells that play a role in extracellular matrix production, in ulcer healing, and in pathophysiological conditions they contribute to chronic inflammation and tumor development. Na+/Ca2+ exchangers (NCX) are known to have a crucial role in Ca2+ homeostasis of contractile cells, however, no information is available concerning the role of NCX in the proliferation and migration of gastrointestinal myofibroblasts. In this study, our aim was to investigate the role of NCX in the Ca2+ homeostasis, migration, and proliferation of human gastrointestinal myofibroblasts, focusing on human gastric myofibroblasts (HGMs). We used microfluorometric measurements to investigate the intracellular Ca2+ and Na+ concentrations, PCR analysis and immunostaining to show the presence of the NCX, patch clamp for measuring NCX activity, and proliferation and migration assays to investigate the functional role of the exchanger. We showed that 53.0±8.1% of the HGMs present Ca2+ oscillations, which depend on extracellular Ca2+ and Na+, and can be inhibited by NCX inhibitors. NCX1, NCX2, and NCX3 were expressed at both mRNA and protein levels in HGMs, and they contribute to the intracellular Ca2+ and Na+ homeostasis as well, regardless of the oscillatory activity. NCX inhibitors significantly blocked the basal and insulin-like growth factor II-stimulated migration and proliferation rates of HGMs. In conclusion, we showed that NCX plays a pivotal role in regulating the Ca2+ homeostasis, migration, and proliferation of HGMs. The inhibition of NCX activity may be a potential therapeutic target in hyperproliferative gastric diseases.

DermAll nanomedicine for allergen-specific immunotherapy.

Allergen-specific immunotherapy (ASIT) the only disease-modifying treatment for IgE-mediated allergies is characterized with long treatment duration and high risk of side effects. We investigated the safety, immunogenicity and efficacy of a novel ASIT, called DermAll, in an experimental allergic rhinitis model. We designed and characterized DermAll-OVA, a synthetic plasmid pDNA/PEIm nanomedicine expressing ovalbumin (OVA) as model allergen. DermAll-OVA was administered topically with DermaPrep device to target Langerhans cells. To detect the clinical efficacy of DermAll ASIT we quantified the nasal symptoms and characterized the immunomodulatory activity of DermAll ASIT by measuring cytokine secretion after OVA-stimulation of splenocytes and antibodies from the sera. In allergic mice DermAll ASIT was as safe as Placebo, balanced the allergen-induced pathogenic TH2-polarized immune responses, and decreased the clinical symptoms by 52% [32%, 70%] compared to Placebo. These studies suggest that DermAll ASIT is safe and should significantly improve the immunopathology and symptoms of allergic diseases. FROM THE CLINICAL EDITOR: A novel allergen-specific immunotherapy for IgE-mediated allergies is presented in this paper, using an experimental allergic rhinitis model and a synthetic plasmid pDNA/PEIm nanomedicine expressing ovalbumin as model allergen. Over 50% reduction of symptoms was found as the immune system's balance was favorably altered toward more TH2-polarized immune responses.

Unraveling Transcriptome Profile, Epigenetic Dynamics, and Morphological Changes in Psoriasis-like Keratinocytes: "Insights into Similarity with Psoriatic Lesional Epidermis".

Keratinocytes are one of the primary cells affected by psoriasis inflammation. Our study aimed to delve deeper into their morphology, transcriptome, and epigenome changes in response to psoriasis-like inflammation. We created a novel cytokine mixture to mimic mild and severe psoriasis-like inflammatory conditions in cultured keratinocytes. Upon induction of inflammation, we observed that the keratinocytes exhibited a mesenchymal-like phenotype, further confirmed by increased VIM mRNA expression and results obtained from confocal microscopy. We performed RNA sequencing to achieve a more global view, revealing 858 and 6987 DEGs in mildly and severely inflamed keratinocytes, respectively. Surprisingly, we found that the transcriptome of mildly inflamed keratinocytes more closely mimicked that of the psoriatic epidermis transcriptome than the severely inflamed keratinocytes. Genes involved in the IL-17 pathway were a major contributor to the similarities of the transcriptomes between mildly inflamed KCs and psoriatic epidermis. Mild and severe inflammation led to the gene regulation of epigenetic modifiers such as HATs, HDACs, DNMTs, and TETs. Immunofluorescence staining revealed distinct 5-hmC patterns in inflamed versus control keratinocytes, and consistently low 5-mC intensity in both groups. However, the global DNA methylation assay detected a tendency of decreased 5-mC levels in inflamed keratinocytes versus controls. This study emphasizes how inflammation severity affects the transcriptomic similarity of keratinocytes to psoriatic epidermis and proves dynamic epigenetic regulation and adaptive morphological changes in inflamed keratinocytes.

[Written and pictorial content in magazines and their possible relationship to eating disorders]. / A magazinokban megjeleno írott és képi tartalmak evészavarokkal való lehetséges kapcsolata.

UNLABELLED: In the current study we reviewed the literature on studies exploring the magazine reading frequency, written and pictorial contents appearing in magazines and their connection to eating disorders. Reading different fashion and fitness magazines has effect on readers through several indirect and direct factors and through trustable and false information. They affect readers' body satisfaction, self-esteem, eating habits and more generally their health behavior. Different theories have been explained to account for these associations and several other studies examined empirically the connection between the frequency of magazine reading and eating disorders, as well as the symptoms leading to eating disorders. METHODS: We analyzed and summarized articles between 1975 and 2009 from online databases. We used the following sources: Science Direct (http://www.sciencedirect.com/), Springer-Verlag GmbH (http://www.springerlink.com/) and SAGE Publications Ltd (http://online.sagepub. com/). RESULTS: The pictorial and written magazine contents were associated with the development and maintenance of eating disorders or with symptoms that might lead to eating disorders. The publications compared to previous years featured an increased number of advertisements for unhealthy foods, for unhealthy radical diet plans and exercise programs. Furthermore the magazines contained conflicting messages about nutrition, body functions and eating disorders. CONCLUSION: Written and pictorial magazine contents, messages might increase the risk for development of eating disorders, especially in vulnerable individuals.

Transcriptional Analysis-Based Alterations Affecting Neuritogenesis of the Peripheral Nervous System in Psoriasis.

An increasing amount of evidence indicates the critical role of the cutaneous nervous system in the initiation and maintenance of psoriatic skin lesions by neurogenic inflammation. However, molecular mechanisms affecting cutaneous neurons are largely uncharacterized. Therefore, we reanalyzed a psoriatic RNA sequencing dataset from published transcriptome experiments of nearly 300 individuals. Using the Ingenuity Pathway Analysis software, we associated several hundreds of differentially expressed transcripts (DETs) to nervous system development and functions. Since neuronal projections were previously reported to be affected in psoriasis, we performed an in-depth analysis of neurite formation-related process. Our in silico analysis suggests that SEMA-PLXN and ROBO-DCC-UNC5 regulating axonal growth and repulsion are differentially affected in non-lesional and lesional skin samples. We identified opposing expressional alterations in secreted ligands for axonal guidance signaling (RTN4/NOGOA, NTNs, SEMAs, SLITs) and non-conventional axon guidance regulating ligands, including WNT5A and their receptors, modulating axon formation. These differences in neuritogenesis may explain the abnormal cutaneous nerve filament formation described in psoriatic skin. The processes also influence T-cell activation and infiltration, thus highlighting an additional angle of the crosstalk between the cutaneous nervous system and the immune responses in psoriasis pathogenesis, in addition to the known neurogenic pro-inflammatory mediators.

Cutibacterium acnes regulates the epidermal barrier properties of HPV-KER human immortalized keratinocyte cultures.

Our skin provides a physical barrier to separate the internal part of our body from the environment. Maintenance of complex barrier functions is achieved through anatomical structures in the skin, the stratified squamous epithelium specialized junctional organelles, called tight junctions (TJs). Several members of our microbial communities are known to affect the differentiation state and function of the colonized organ. Whether and how interactions between skin cells and cutaneous microbes, including Cutibacterium acnes (C. acnes), modify the structure and/or function of our skin is currently only partly understood. Thus, in our studies, we investigated whether C. acnes may affect the epidermal barrier using in vitro model systems. Real-time cellular analysis showed that depending on the keratinocyte differentiation state, the applied C. acnes strains and their dose, the measured impedance values change, together with the expression of selected TJ proteins. These may reflect barrier alterations, which can be partially restored upon antibiotic-antimycotic treatment. Our findings suggest that C. acnes can actively modify the barrier properties of cultured keratinocytes, possibly through alteration of tight cell-to-cell contacts. Similar events may play important roles in our skin, in the maintenance of cutaneous homeostasis.

Cartilage Oligomeric Matrix Protein Negatively Influences Keratinocyte Proliferation via α5ß1-Integrin: Potential Relevance of Altered Cartilage Oligomeric Matrix Protein Expression in Psoriasis.

In psoriasis, nonlesional skin shows alterations at the dermal-epidermal junction compared with healthy skin. Cartilage oligomeric matrix protein (COMP) is part of the papillary dermis of healthy skin, and its expression has not yet been studied in psoriatic skin. In this study, we found that COMP localization extended deeper into the dermis and formed a more continuous layer in psoriatic nonlesional skin compared with healthy skin, whereas in psoriatic lesions, COMP showed a partially discontinuous deposition at the dermal-epidermal junction. COMP and ß1-integrin showed strong colocalization in nonlesional skin, where the laminin layer within the basement membrane is discontinuous. In in vitro models, the presence of exogenous COMP decreased the proliferation rate of keratinocytes, and this proliferation-suppressing effect was diminished by blocking α5ß1-integrin. Our results suggest that COMP can interact with α5ß1-integrin of basal keratinocytes through the disrupted basement membrane, and this interaction might stabilize the epidermis in the nonlesional state by contributing to the suppression of keratinocyte proliferation. The antiproliferative effect of COMP is likely to be relevant to other skin diseases in which chronic nonhealing wounds are coupled with massive COMP accumulation.