Non-lesional Psoriatic Skin Research Articles

Epidermal proteomics demonstrates Elafin as a psoriasis-specific biomarker and highlights increased anti-inflammatory activity around psoriatic plaques.

Eczema and psoriasis are common diseases. Despite both showing active epidermal contribution to the inflammatory process, their molecular aetiology and pathological mechanisms are different. Further molecular insight into these differences is therefore needed to enable effective future diagnostic and treatment strategies. The majority of our mechanistic and clinical understanding of psoriasis and eczema is derived from RNA, immunohistology and whole skin biopsy data. In this study, non-invasive epidermal sampling of lesional, perilesional and non-lesional skin from diseased and healthy skin was used to perform an in depth proteomic analysis of epidermal proteins. Our findings confirmed the psoriasis-associated cytokine IL-36γ as an excellent protein biomarker for lesional psoriasis. However, ELISA and ROC curve analysis of 53 psoriasis and 42 eczema derived samples showed that the sensitivity and specificity were outperformed by elastase-specific protease inhibitor, elafin. Of note, elafin was also found upregulated in non-lesional psoriatic skin at non-predilection sites demonstrating inherent differences between the non-involved skin of healthy and psoriatic individuals. Mass spectrometry and ELISA analysis also demonstrated the upregulation of the anti-inflammatory molecule IL-37 in psoriatic perilesional but not lesional skin. The high expression of IL-37 surrounding psoriatic plaque may contribute to the sharp demarcation of inflammatory morphology changes observed in psoriasis. This finding was also specific for psoriasis and not seen in atopic dermatitis or autoimmune blistering perilesional skin. Our results confirm IL-36γ and add elafin as robust, hallmark molecules distinguishing psoriasis and eczema-associated inflammation even in patients under systemic treatment. Overall, these findings highlight the potential of epidermal non-invasive sampling and proteomic analysis to increase our diagnostic and pathophysiologic understanding of skin diseases. Moreover, the identification of molecular differences in healthy-looking skin between patients and healthy controls highlights potential disease susceptibility markers and proteins involved in the initial stages of disease.

HGF, HNRPD, and sFLT1 Interfere with the Induction of VEGF in Patients with Severe Psoriasis.

Restructuring of dermal microcapillaries is one of the hallmarks of plaque psoriasis. To control the proliferation of vascular endothelial cells, vascular endothelial growth factor (VEGF) promotes the remodeling of the existing blood vessels and angiogenesis. This study aimed to explain the lowering protein and mRNA levels of VEGF in lesional skin of patients with severe psoriasis (the Psoriasis Area and Severity Index, PASI > 25). Using the method of qPCR, we assessed the expression of VEGF mRNA in lesional and nonlesional psoriatic skin. Using ELISA, we also compared the levels of VEGF in skin homogenates of psoriasis patients and healthy volunteers. We found that the exacerbation of psoriasis induced VEGF on mRNA and protein levels 12 and 20 times, respectively. We also confirmed a strong correlation between VEGF and PASI score in patients with PASI < 25. In addition, we showed that several factors, namely HGF, HNRPD, and sFLT1 interfere with the biosynthesis of VEGF in skin lesions of patients with PASI > 25%. Thus, using VEGF as a biomarker to monitor the disease shall be done cautiously in patients with severe psoriasis.

Discovery of biomarkers in the psoriasis through machine learning and dynamic immune infiltration in three types of skin lesions.

Psoriasis is a chronic skin disease characterized by unique scaling plaques. However, during the acute phase, psoriatic lesions exhibit eczematous changes, making them difficult to distinguish from atopic dermatitis, which poses challenges for the selection of biological agents. This study aimed to identify potential diagnostic genes in psoriatic lesions and investigate their clinical significance. GSE182740 datasets from the GEO database were analyzed for differential analysis; machine learning algorithms (SVM-RFE and LASSO regression models) are used to screen for diagnostic markers; CIBERSORTx is used to determine the dynamic changes of 22 different immune cell components in normal skin lesions, psoriatic non-lesional skin, and psoriatic lesional skin, as well as the expression of the diagnostic genes in 10 major immune cells, and real-time quantitative polymerase chain reaction (RT-qPCR) and immunohistochemistry are used to validate results. We obtained 580 differentially expressed genes (DEGs) in the skin lesion and non-lesion of psoriasis patients, 813 DEGs in mixed patients between non-lesions and lesions, and 96 DEGs in the skin lesion and non-lesion of atopic dermatitis, respectively. Then 144 specific DEGs in psoriasis via a Veen diagram were identified. Ultimately, UGGT1, CCNE1, MMP9 and ARHGEF28 are identified for potential diagnostic genes from these 144 specific DEGs. The value of the selected diagnostic genes was verified by receiver operating characteristic (ROC) curves with expanded samples. The the area under the ROC curve (AUC) exceeded 0.7 for the four diagnosis genes. RT-qPCR results showed that compared to normal human epidermis, the expression of UGGT1, CCNE1, and MMP9 was significantly increased in patients with psoriasis, while ARHGEF28 expression was significantly decreased. Notably, the results of CIBERSORTx showed that CCNE1 was highly expressed in CD4+ T cells and neutrophils, ARHGEF28 was also expressed in mast cells. Additionally, CCNE1 was strongly correlated with IL-17/CXCL8/9/10 and CCL20. Immunohistochemical results showed increased nuclear expression of CCNE1 in psoriatic epidermal cells relative to normal. Based on the performance of the four genes in ROC curves and their expression in immune cells from patients with psoriasis, we suggest that CCNE1 possess higher diagnostic value.

Reappraisal of psoriasis pathogenesis: the role of TEAD4 expression in keratinocytes.

Psoriasis is an immune-mediated inflammatory skin disorder with a multifaceted pathogenesis. Immune dysregulation and immune cell dysfunction are among the mechanisms involved. TEA domain family member 4 (TEAD4) is suggested to play a role in psoriasis development. TEAD4 expression in keratinocytes may have a chemotactic effect and could disturb the function of FOXP3-positive T lymphocytes. This study aimed to evaluate the expressions of TEAD4 and FOXP3 in lesional, nonlesional psoriatic, and healthy skin and assess the clinical impact of their expression. This case-control study included 32 cases with psoriasis vulgaris and 32 control groups. Hematoxylin and eosin-stained slides were examined to evaluate the histopathological findings. Moreover, other sections were immunohistochemically stained with FOXP3 and TEAD4. FOXP3 was expressed in inflammatory cells in 56.5, 37.5, and 12.5% of lesional, nonlesional, and healthy skin, whereas it was entirely negative in the keratinocytes. TEAD4 was expressed in keratinocytes in 93.7 and 46.9% of lesional and nonlesional skin, while negative in healthy skin. Significant differences were observed between their lesional, nonlesional, and healthy skin expressions. Furthermore, FOXP3 expression in lesional skin was significantly associated with early onset (P = 0.016), low PASI score (P = 0.002), mild psoriasis (P = 0.007), and axial affection (P = 0.022), while TEAD4 expression was associated with progressive course (P = 0.032), high PASI score (P = 0.002), severe psoriasis (P = 0.001), severe inflammation (P = 0.001), and progressive course (P = 0.017). TEAD4 expression was higher in lesional than nonlesional skin and absent in healthy skin, suggesting a role in psoriasis development. TEAD4 expression was also associated with severe and progressive psoriasis. This may be mediated by the downregulation of FOXP3 and dysfunction of Treg cells. TEAD4 could serve as a promising therapeutic target in psoriasis.

Expression Dynamics Of Cytokine Genes Is Related To The Apremilast Treatment Effectiveness In Patients With Severe Psoriasis

Background — Psoriasis is an immune-mediated genetic skin disease with a deregulated immune response governed by a proinflammatory cytokine network. Apremilast has demonstrated high safety and tolerability both in clinical trials and in clinical practice. The effectiveness of the apremilast use in clinical practice may differ from major clinical trials. Our study assessed changes in the levels of immune gene expression in patients suffering from severe psoriasis in the course of apremilast treatment in order to investigate the predictors of its effectiveness. Methods — We assessed the expression levels of IFNγ, IRF3, GLIS1, HR, STAT1, STAT3, VEGFA, ICAM1, TNF, IL1α, IL1β, IL4, IL6, IL10, IL11, IL12B, IL17A, IL17F, IL18, IL20, IL21, IL22, IL23A, IL25, IL31, IL33 genes in both lesional and nonlesional skin before the treatment, as well the expression at lesional skin after the treatment. RNA expression was assessed in skin biopsy samples by RT-PCR using TaqMan probes with StepOne5 equipment and normalized with endogenous control. The study included 16 patients diagnosed with a moderate-to-severe or severe psoriasis using clinical examination by a dermatologist. The clinical outcome after 26 weeks of apremilast treatment was assessed with delta PASI, resulting in a patient group with high effectiveness of treatment (delta PASI&gt;75%) and a group including all other patients. Results — We confirmed elevated levels of expression in STAT1, IFNγ, IL1β, IL12B, IL17A, IL17F, IL20, IL21, IL22, and IL23A genes in lesional vs. nonlesional psoriatic skin samples, while GLIS1 gene expression was reduced. The expression levels of cytokine genes after apremilast treatment decreased considerably in cytokines IFNγ, IL1β, IL20, IL21, and IL22; and to a lesser extent in STAT1, IL6, IL17F, IL22 and IL31. In the group of those who effectively responded to treatment with apremilast, a five-to-eleven-fold reduction in the expression level of the IL1B, IL6, and IL17F genes was observed, as compared with other patients. Conclusion — The increased expression of cytokine genes in lesional vs. nonlesional skin was reduced after apremilast treatment of psoriasis. We established that fold changes in the expression of the IL1β, IL6 and IL17F genes during treatment with apremilast were different in groups of patients with different therapy outcomes. Hence, we propose that they are the predictors of the effectiveness of apremilast treatment for severe psoriasis.

Transcriptional Landscape of Repetitive Elements in Psoriatic Skin from Large Cohort Studies: Relevance to Psoriasis Pathophysiology

While studies demonstrating the expression of repetitive elements (REs) in psoriatic skin using RNA-seq have been published before, not many studies have focused on the genome-wide expression patterns using larger cohorts. This study investigated the transcriptional landscape of differentially expressed REs in lesional and non-lesional skin from two previously published large datasets. We observed significant differential expression of REs in lesional psoriatic skin as well as the skin of healthy controls. Significant downregulation of several ERVs, HERVs (including HERV-K) and LINEs was observed in lesional psoriatic skin from both datasets. The upregulation of a small subset of HERV-Ks and Alus in lesional psoriatic skin was also reported. An interesting finding from this expression data was the significant upregulation and overlapping of tRNA repetitive elements in lesional and non-lesional psoriatic skin. The data from this study indicate the potential role of REs in the immunopathogenesis of psoriasis. The expression data from the two independent large study cohorts are powerful enough to confidently verify the differential expression of REs in relation to psoriatic skin pathology. Further studies are warranted to understand the functional impact of these repetitive elements in psoriasis pathogenesis, thereby expanding their significance as a potential targeting pathway for the disease treatment of psoriasis and other inflammatory diseases.

Abnormal basement membrane results in increased keratinocyte-derived periostin expression in psoriasis similar to wound healing

The psoriatic skin resembles wound healing, and it shows abnormalities at the basement membrane (BM), also in the non-lesional skin. Fibroblast-derived dermal periostin has well-known functions in wound healing and Th2-mediated diseases, such as atopic dermatitis. Here we show that serum periostin level was elevated in psoriatic patients, remarkably in the systemically treated ones. Obvious periostin positivity was detected in basal keratinocytes of the non-lesional, lesional, and previously-lesional psoriatic vs. healthy skin. Ex vivo skin models were generated to examine how different skin injuries affect periostin expression during wound healing. Our newly developed cultured salt-split model demonstrated that BM-injury induced periostin expression in basal keratinocytes, and periostin levels in the supernatant were also increased upon healing. In wound healing models, β1-integrin expression was similarly induced. β1-integrin blocking caused reduced periostin expression in in vitro scratch assay, indicating that β1-integrin can mediate periostin production. In contrast to atopic dermatitis, psoriatic basal keratinocytes are in an activated state and show a stable wound healing-like phenotype with the overexpression of periostin. This abnormal BM-induced wound healing as a potential compensatory mechanism can be initiated already in the non-lesional skin present in the lesion and keratinocytes can remain activated in the healed skin.

Altered structure indicating reduced barrier function of lesional compared to non-lesional psoriatic skin-A non-invasive in vivo study of the human stratum corneum with confocal Raman micro-spectroscopy.

Psoriasis, one of the most common skin diseases affecting roughly 2%-3% of the world population, is associated with a reduced skin barrier function (SBF) that might play an important role in its pathophysiology. The SBF is provided primarily by the stratum corneum (SC) of the skin. Previous studies have revealed a higher trans-epidermal water loss, lower hydration, abnormal concentration and composition of intercellular lipids, as well as alterations in secondary keratin structure in the psoriatic SC. We compared on molecular level lesional psoriatic skin (LPS) with non-lesional psoriatic skin (nLPS) from 19 patients non-invasively in vivo, using confocal Raman micro-spectroscopy. By analysing the corresponding Raman spectra, we determined SBF-defining parameters of the SC depth-dependently. Our results revealed a lower total lipid concentration, a shift of lamellar lipid organisation towards more gauche-conformers and an increase of the less dense hexagonal lateral packing of the intercellular lipids in LPS. Furthermore, we observed lower natural moisturising factor concentration, lower total water as well as a strong tendency towards less strongly bound and more weakly bound water molecules in LPS. Finally, we detected a less stable secondary keratin structure with increased β-sheets, in contrast to the tertiary structure, showing a higher degree of folded keratin in LPS. These findings clearly suggest structural differences indicating a reduced SBF in LPS, and are discussed in juxtaposition to preceding outcomes for psoriatic and healthy skin. Understanding the alterations of the psoriatic SC provides insights into the exact pathophysiology of psoriasis and paves the way for optimal future treatments.

Comparative analysis of cyclin-dependent kinase 2 density by immunohistochemistry in lesional versus nonlesional psoriatic skin

Background Psoriasis is a noninfectious, inflammatory, and hyperproliferative skin disorder. Cyclin-dependent kinase 2 (CDK2) is a serine-threonine protein kinase that plays a role in the transition of G1/S, the initiation of DNA synthesis, and the regulation of the S phase exit in the cell cycle. CDK2 is uniformly expressed in healthy human epidermis being located mainly in the cytoplasm and nuclei of basal keratinocytes.Objective To compare the CDK2 density by immunohistochemistry in lesional versus nonlesional psoriatic skin and normal control and to correlate its expression with disease severity.Patients and methods This study was conducted on 30 patients with plaque psoriasis and 20 age-matched and sex-matched controls. Biopsies were obtained from the active plaque (lesional) and nonlesional skin of the patients and normal controls. CDK2 density was assessed by counting immunohistochemically positive nuclei in 1000 suprabasal keratinocytes at ×400 power fields.Results CDK2 was negative in normal control skin (no positive nuclear staining was seen in suprabasal keratinocytes). Meanwhile, the psoriatic group showed diffuse nuclear positivity in suprabasal cells. The density was significantly higher in lesional versus nonlesional skin. CDK2 density in lesional and nonlesional skin showed a statistically significant correlation with Psoriasis Area and Severity Index score (r=0.820 and 0.683, P<0.001 and <0.001, respectively).Conclusion CDK2 density is high in plaque psoriatic epidermis more than in nonlesional and control skin, and this was positively correlated with disease severity. It indicates that it may play a role in the development of psoriasis and may be a potential therapeutic target.

373 Abnormal type VII collagen expression in non-lesional psoriatic skin

The healthy-looking non-lesional (NL) psoriatic skin already carries some alterations. These alterations include extracellular matrix defects such as the disruption of laminin networks, which may lead to impaired keratinocyte adhesion to the basal membrane. This process is associated with aberrant expression of the α5β1 integrin complex and the extradomain-A-containing fibronectin (EDA+FN) around basal keratinocytes. In our previous work, in NL psoriatic skin the expression of EDA+FN was increased compared to healthy (H) skin.

Noninvasive Tape-Stripping with High-Resolution RNA Profiling Effectively Captures a Preinflammatory State in Nonlesional Psoriatic Skin

Tape stripping is a minimally invasive, nonscarring method that can be utilized to assess gene expression in the skin but is infrequently used given technical constraints. By comparing different tape stripping technologies and full-thickness skin biopsy results of lesional and nonlesional psoriatic skin from the same patients, we demonstrate that tape stripping with optimized high-resolution transcriptomic profiling can be used to effectively assess and characterize inflammatory responses in the skin. Upon comparison with single-cell RNA-sequencing data from psoriatic full-thickness skin biopsies, we illustrate that tape-stripping efficiently captures the transcriptome of the upper layers of the epidermis with sufficient resolution to assess the molecular components of the feed-forward immune amplification pathway in psoriasis. Notably, nonlesional psoriatic skin sampled by tape stripping demonstrates activated, proinflammatory changes when compared to healthy control skin, suggesting a prepsoriatic state, which is not captured on full-thickness skin biopsy transcriptome profiling. This work illustrates an approach to assess inflammatory response in the epidermis by combining noninvasive sampling with high throughput RNA-sequencing, providing a foundation for biomarker discoveries and mechanism of action studies for inflammatory skin conditions.

MicroRNA profiling of psoriatic skin identifies 11 miRNAs associated with disease severity.

MicroRNAs (miRNAs) are small non-coding RNAs that have emerged as central regulators of gene expression and powerful biomarkers of disease. Much is yet unknown about their role in psoriasis pathology. To globally characterize the miRNAome of psoriatic skin, skin biopsies were collected from psoriatic cases (n=75) and non-psoriatic controls (n=46) and RNA sequenced. Count data were meta-analysed with a previously published dataset (cases, n=24, controls, n=20), increasing the number of psoriatic cases fourfold from previously published studies. Differential gene expression analyses were performed comparing lesional psoriatic (PP), non-lesional psoriatic (PN) and control (NN) skin. Further, functional enrichment and cell-specific analyses were performed. Across all contrasts, we identified 439 significantly differentially expressed miRNAs (DEMs), of which 85 were novel for psoriasis and 11 were related to disease severity. Meta-analyses identified 20 DEMs between PN and NN, suggesting an inherent change in the constitution of all skin in psoriasis. By integrating the miRNA transcriptome with mRNA target interactions, we identified several functionally enriched terms, including "thyroid hormone signalling," "insulin resistance" and various infectious diseases. Cell-specific expression analyses revealed that the upregulated DEMs were enriched in epithelial and immune cells. This study provides the most comprehensive overview of the miRNAome in psoriatic skin to date and identifies a miRNA signature related to psoriasis severity. Our results may represent molecular links between psoriasis and related comorbidities and have outlined potential directions for future functional studies to identify biomarkers and treatment targets.

CXCL10 and its related key genes as potential biomarkers for psoriasis: Evidence from bioinformatics and real-time quantitative polymerase chain reaction.

Although several studies have attempted to investigate the etiology of and mechanism underlying psoriasis, the precise molecular mechanism remains unclear. Our study aimed to explore the molecular mechanism underlying psoriasis based on bioinformatics.GSE30999, GSE34248, GSE41662, and GSE50790 datasets were obtained from the Gene Expression Omnibus database. The Gene Expression Omnibus profiles were integrated to obtain differentially expressed genes in R software. Then a series of analyses was performed, such as Gene Ontology annotation, Kyoto Encyclopedia of Genes and Genomes pathway analysis, protein-protein interaction network analysis, among others. The key genes were obtained by CytoHubba, and validated by real-time quantitative polymerase chain reaction.A total of 359 differentially expressed genes were identified between 270 paired lesional and non-lesional skin groups. The common enriched pathways were nucleotide-binding and oligomerization domain-like receptor signaling pathway, and cytokine-cytokine receptor interaction. Seven key genes were identified, including CXCL1, ISG15, CXCL10, STAT1, OASL, IFIT1, and IFIT3. These key genes were validated as upregulated in the 4 datasets and M5-induced HaCaT cells.Our study identified 7 key genes, namely CXCL1, ISG15, CXCL10, STAT1, OASL, IFIT1, and IFIT3, and 2 mostly enriched pathways (nucleotide-binding and oligomerization domain-like receptor signaling pathway, and cytokine-cytokine receptor interaction) involved in psoriatic pathogenesis. More importantly, CXCL1, ISG15, STAT1, OASL, IFIT1, IFIT3, and especially CXCL10 may be potential biomarkers. Therefore, our findings may bring a new perspective to the molecular mechanism underlying psoriasis and suggest potential biomarkers.

Cytokine responses in nonlesional psoriatic skin as clinical predictor to anti-TNF agents

A major issue with the current management of psoriasis is our inability to predict treatment response. Our aim was to evaluate the ability to use baseline molecular expression profiling to assess treatment outcome for patients with psoriasis. We conducted a longitudinal study of 46 patients with chronic plaque psoriasis treated with anti-TNF agent etanercept, and molecular profiles were assessed in more than 200 RNA-seq samples. We demonstrated correlation between clinical response and molecular changes during the course of the treatment, particularly for genes responding to IL-17A/TNF in keratinocytes. Intriguingly, baseline gene expressions in nonlesional, but not lesional, skin were the best marker of treatment response at week 12. We identified USP18, a known regulator of IFN responses, as positively correlated with Psoriasis Area and Severity Index (PASI) improvement (P= 9.8×10-4) and demonstrate its role in regulating IFN/TNF responses in keratinocytes. Consistently, cytokine gene signatures enriched in baseline nonlesional skin expression profiles had strong correlations with PASI improvement. Using this information, we developed a statistical model for predicting PASI75 (ie, 75% of PASI improvement) at week 12, achieving area under the receiver-operating characteristic curve value of 0.75 and up to 80% accurate PASI75 prediction among the top predicted responders. Our results illustrate feasibility of assessing drug response in psoriasis using nonlesional skin and implicate involvement of IFN regulators in anti-TNF responses.

The Psoriatic Nonlesional Skin: A Battlefield between Susceptibility and Protective Factors

In the last two decades, large-scale gene-expression studies on psoriatic skin samples revealed that even though nonlesional skin is macroscopically identical to healthy skin, it harbors several molecular differences. Originally, these molecular differences were thought to represent susceptibility factors for plaque formation. However, we review in this paper the several factors of immune regulation and structural alteration that are specific for the nonlesional skin and serve as protective factors by counteracting plaque formation and contributing to the maintenance of the nonlesional phenotype.

Psoriasis is a disease of the entire skin: non-lesional skin displays a prepsoriasis phenotype.

Psoriasis is a multifactorial skin pathology resulting from genetic susceptibility and environmental triggers that lead to epidermal and immune dysfunction. There is now strong evidence that non-lesional (NL) psoriatic skin, despite its normal appearance, represents an intermediate state between healthy and lesional skin. Changes observed in NL skin mainly affect the skin barrier, keratinocytes, innate and adaptive immune responses, the microbiota and neurogenic tissue innervation. Several epidermal barrier defects are commonly observed in NL skin compared to healthy skin, including an elevated pH, delayed barrier function repair after injury and lower expression of epidermal differentiation complex proteins. NL keratinocytes also show a predisposition for activation and proliferation, and an increased sensitivity to cytokine or microbial triggers, probably linked to their unique transcriptome and proteome, associated with their intermediate state between healthy and lesional cells. In addition, the accumulation of pathogenic IL-17-producing resident memory T cells, which can (re)instigate the formation of new lesions, characterises both the NL and never-lesional skin of patients with psoriasis. Although the contribution of NL skin dysbiosis to psoriasis pathophysiology remains to be clarified, the expression of numerous pruritogenic mediators appears to be involved in disease progression due to an iterative itch-scratch cycle. In summary, the NL skin of patients with psoriasis exhibits numerous hallmarks of dormant psoriasis. The fact that these alterations are mostly located in the epidermis suggests that they are readily accessible to topical treatments, which could prevent the recurrence/spread of this chronic disease.

The HSP90 inhibitor RGRN‐305 exhibits strong immunomodulatory effects in human keratinocytes

Keratinocytes are the key cellular target for IL-17A-mediated effects in psoriasis and HSP90 is important for IL-17A-mediated signalling. RGRN-305 is a novel HSP90 inhibitor reported to reduce psoriatic phenotypes in preclinical animal models. The aim of this study was to investigate the effect of RGRN-305 on a psoriasis-like inflammatory response in human keratinocytes in vitro. Using RT-qPCR, we demonstrated a significantly increased expression of the HSP90 isoforms HSP90AB1, HSP90B1 and TRAP1 in lesional compared with non-lesional psoriatic skin. In a psoriasis-like setting where keratinocytes were stimulated with TNFα and/or IL-17A, we analysed the mRNA expression using the NanoString nCounter technology and demonstrated that the HSP90 inhibitor RGRN-305 significantly reduced the IL-17A- and TNFα-induced gene expression of a number of proinflammatory genes, including the psoriasis-associated genes CCL20, NFKBIZ, IL36G and IL23A. In agreement with the mRNA data, the protein level of CCL20, IκBζ and IL-36γ were inhibited by RGRN-305 as demonstrated by western blotting and ELISA. Interestingly, when keratinocytes were stimulated with a TLR3 agonist, RGRN-305 also demonstrated potent immunomodulatory effects, significantly inhibiting poly(I:C)-induced expression of the proinflammatory genes TNFα, IL1B, IL6 and IL23A. Taken together, our data support a role for HSP90 not only in the pathogenesis of psoriasis, but also in broader immune responses. Therefore, HSP90 provides an attractive target for the treatment of psoriasis and other diseases where the innate immune system plays an important role.

Could basement membrane alterations, resembling micro-wounds at the dermo-epidermal junction in psoriatic non-lesional skin, make the skin susceptible to lesion formation?

Current data suggest that tissue microenvironment control immune functions. Therefore, understanding the tissue environment in which immune activation occurs will enhance our capability to interfere with abnormal immune pathology. Here, we argue that studying the constitutively abnormal functions of clinically uninvolved psoriatic skin in patients with plaque type psoriasis is very important to better understand psoriasis pathobiology, because non-lesional skin provides the tissue environment in which the psoriatic lesion develops. A key question in psoriasis is what initiates the abnormal, uncontrolled immune activation in the first place and the answer may lie in the skin. In light of this concept, we summarize abnormalities at the dermal-epidermal junction region which shows a special "non-healing-like" micro-wound phenotype in the psoriatic non-lesional skin that may act as a crucial susceptibility factor in the development of the disease.

Distribution of Malassezia species on the skin of patients with psoriasis

IntroductionMalassezia species can induce the expression of interleukin-17 (IL-17), which plays an important role in the inflammatory and immune response in psoriasis (PS). The purpose of this study was to investigate the Malassezia species composition in patients with PS and healthy individuals and explore the role of Malassezia species in the pathogenesis of PS. Materials and methodsA total of 28 patients with PS and 10 age- and sex-matched healthy individuals participated in this study. Specimens collected from the lesional and non-lesional skin of patients with PS and the skin of healthy individuals were analyzed by using nested PCR. ResultsThe relative abundance of Malassezia species was 84.96% in healthy subjects, more than twice that in patients with PS (P<0.01). M. restricta (43.09%) and M. globosa (41.38%) were the main Malassezia species in patients with PS followed by M. furfur (4.84%) and M. sympodialis (2.49%). M. sympodialis accounted for 18. 81% of the Malassezia species in healthy subjects, which was nearly eight times higher than in patients with PS (P<0.01). Further, M. furfur was detected both on lesional and non-lesional psoriatic skin, but it was not found on the skin of healthy individuals. ConclusionsThe Malassezia species composition in patients with PS differed from that of healthy individuals. M. restricta and M. globosa were the main Malassezia species in patients with PS.

MiR-183-3p suppresses proliferation and migration of keratinocyte in psoriasis by inhibiting GAB1

BackgroundMicroRNAs (miRNAs) target genes involved in the hyperproliferation of keratinocytes or immune dysfunction of psoriasis. This study prospectively determined the involvement of miR-183-3p in the pathogenesis of psoriasis.MethodsDifferentially expressed miR-183-3p between psoriatic lesional and non-lesional skin were determined by quantitative RT-PCR and in situ hybridization (ISH). CCK8 and wound healing assays were performed to assess cell viability and migration of human keratinocyte cell line (HaCaT). The target of miR-183-3p was validated by luciferase activity assay.ResultsLower miR-183-3p expression was observed in psoriatic lesional skin compared to psoriatic non-lesional skin. MiR-183-3p over-expression inhibited the viability and migration of HaCaT cells, while inhibition of miR-183-3p promoted the viability and migration of HaCaT cells. Moreover, miR-183-3p could bind to the 3′ UTR of GAB1 (growth factor receptor binding 2-associated binding protein 1) and decrease the mRNA and protein expression of GAB1 in HaCaT cells. In addition, higher GAB1 expression was observed in psoriatic lesional skin than psoriatic non-lesional skin.ConclusionMiR-183-3p exhibited inhibition property in the proliferation and migration of HaCaT cells via down-regulation of GAB1, suggesting the potential therapeutic strategy for psoriasis.