Epidermis In Psoriasis Research Articles

Downregulation of Ebp1Khib210 promotes keratinocyte proliferation through induction of TIF-IA-mediated rRNA synthesis.

Psoriasis is a prevalent chronic inflammatory dermatosis characterized by excessive proliferation of keratinocytes. Protein lysine 2-hydroxyisobutyrylation (Khib) is a newly identified post-translational modification that regulates various biological processes. Abnormal Khib modification has been closely associated with the development of autoimmune diseases. To investigate the abnormal Khib profile and its pathogenic role in psoriasis. We utilized liquid chromatography-tandem mass spectrometry to analyze Khib-modified proteins in the epidermis of psoriasis and healthy controls. Mutated cells and mice with downregulated Ebp1Khib210 were generated to investigate its functional effects in psoriasis. The omic analysis revealed dysregulation of Khib modification in psoriatic lesions, exhibiting a distinct profile compared to controls. We observed the downregulation of Ebp1Khib210 in psoriatic lesions and IMQ-induced psoriatic mice. Notably, the expression of Ebp1Khib210 was upregulated in psoriatic patients following effective treatment. Decreased Ebp1Khib210 enhanced keratinocyte viability, proliferation, and survival while inhibiting apoptosis in vitro. Additionally, Pa2g4K210A mice with downregulated Ebp1Khib210 exhibited more severe psoriatic lesions and enhanced keratinocyte proliferation. Moreover, we found that Ebp1K210A mutation increased the interaction between Ebp1 and nuclear Akt, thereby inhibiting MDM2-mediated TIF-IA ubiquitination, and resulting to increased rRNA synthesis and keratinocyte proliferation. The downregulation of Ebp1Khib210 was attributed to inflammation-induced increases in HDAC2 expression. Our findings demonstrate that downregulation of Ebp1Khib210 promotes keratinocyte proliferation through modulation of Akt signaling and TIF-IA-mediated rRNA synthesis. These insights into Khib modification provide a better understanding of the pathogenesis of psoriasis and suggest potential therapeutic targets.

The Unknown Role of Periostin in Psoriatic Epidermal Hyperplasia.

Psoriasis is an inflammatory skin disease that affects 1-2% of the general population. The pathomechanism is based on type 1 immunological reactions. Hyperplasia of the epidermis in psoriasis is a result of disrupted epidermal architecture due to increased synthesis and expression of extracellular matrix proteins. In our study, we analyzed the involvement of periostin (POSTN) in the pathogenesis of psoriasis, as one of the extracellular matrix proteins belonging to the fasciclin family. The study group consisted of 70 patients with psoriasis, while the control group comprised 30 healthy individuals. The serum concentrations of POSTN, Il-6, Il-17, Il-22, TNF-α and IFN-γ were measured in all participants. The severity of psoriasis was determined using the PASI (Psoriasis Area and Severity Index) score. The presence of POSTN in biopsy samples of 50 patients was assessed using the direct immunofluorescence method. The results were subjected to statistical analysis. The serum concentrations of POSTN, Il-6, Il-17, Il-22, TNF-α and IFN-γ in the study group are significantly higher than in the control group. Positive correlation has been demonstrated between the PASI score and the investigated cytokines, but not with POSTN. There was no statistically significant correlation between the POSTN level and the cytokines levels. POSTN deposits were localized in the epidermis in 66% of patients with psoriasis. The role of POSTN in the pathogenesis of psoriasis remains unclear. The mechanisms inducing the synthesis and expression of POSTN in psoriatic skin are not yet fully understood. Further research is needed to enhance our understanding of the mechanism underlying epidermal hyperplasia in psoriasis.

The Long Noncoding RNA LINC00958 Is Induced in Psoriasis Epidermis and Modulates Epidermal Proliferation

Psoriasis is a common, immune-mediated skin disease characterized by epidermal hyperproliferation and chronic skin inflammation. Long noncoding RNAs are >200 nucleotide-long transcripts that possess important regulatory functions. To date, little is known about the contribution of long noncoding RNAs to psoriasis. In this study, we identify LINC00958 as a long noncoding RNA overexpressed in keratinocytes (KCs) from psoriasis skin lesions, in a transcriptomic screen performed on KCs sorted from psoriasis and healthy skin. Increased levels of LINC00958 in psoriasis KCs were confirmed by RT-qPCR and single-molecule in situ hybridization. Confocal microscopy and analysis of subcellular fractions showed that LINC00958 is mainly localized in the cytoplasm of KCs. IL-17A, a key psoriasis cytokine, induced LINC00958 in KCs through C/EBP-β and the p38 pathway. The inhibition of LINC00958 led to decreased proliferation as measured by Ki-67 expression, live cell analysis imaging, and 5-ethynyl-2-deoxyuridine assays. Transcriptomic analysis of LINC00958-depleted KCs revealed enrichment of proliferation- and cell cycle‒related genes among differentially expressed transcripts. Moreover, LINC00958 depletion led to decreased basal and IL-17A‒induced phosphorylation of p38. Furthermore, IL-17A‒induced KC proliferation was counteracted by the inhibition of LINC00958. In summary, our data support a role for the IL-17A‒induced long noncoding RNA, LINC00958, in the pathological circuits of psoriasis by reinforcing IL-17A‒induced epidermal hyperproliferation.

UBE2L3 Reduces TRIM21 Expression and IL-1β Secretion in Epidermal Keratinocytes and Improves Psoriasis-Like Skin

Proinflammatory cytokines, such as IL-1β, are important mediators of psoriasis. UBE2L3, an E2 enzyme, is thought to be an indirect target of IL-1β secretion by binding to ubiquitin ligases such as TRIM21. However, its role in psoriasis remains unknown. In this study, we found that UBE2L3 expression was decreased in psoriatic epidermis, whereas caspase 1 and IL-1β signaling were strongly activated. When normal human epidermal keratinocytes were stimulated with nigericin, adenosine triphosphate, and poly(dA:dT), downregulation of UBE2L3 and increased secretion of IL-1β were observed. Treatment with a caspase 1 inhibitor reversed the decrease in the level of UBE2L3. In addition, UBE2L3 overexpression reduced TRIM21, decreased signal transducer and activator of transcription 3 pathway activity, and reduced the level of the IL-1β precursor (pro‒IL-1β). Consistently, silencing UBE2L3 enhanced TRIM21 expression, signal transducer and activator of transcription 3 activation, and pro‒IL-1β production. Finally, in an imiquimod-induced mouse model, UBE2L3 reduction and caspase 1 activation were localized in the epidermis, whereas overexpression of UBE2L3 ameliorated psoriasis-like lesions and reduced pro‒IL-1β and mature IL-1β levels in the epidermis. Thus, UBE2L3 may be a protective biomarker that regulates IL-1β and inhibits TRIM21 in the epidermis of psoriasis.

318 The long non-coding RNA LINC00958 is overexpressed in psoriasis epidermis and induces keratinocyte proliferation

Psoriasis is a common, chronically relapsing inflammatory skin disease characterized by epidermal hyperproliferation. LncRNAs are >200 nucleotide long transcripts, which do not code for protein but possess diverse regulatory functions. To date, little is known about the contribution of lncRNAs to psoriasis. Here, we identified lncRNAs with altered expression using transcriptomic profiling on epidermal cells sorted from psoriasis and healthy skin. LINC00958 was identified as a lncRNA overexpressed in keratinocytes from psoriasis skin lesions, and confirmed by RT-qPCR and single molecule in situ hybridization.

Thioredoxin-interacting protein regulates keratinocyte differentiation: Implication of its role in psoriasis.

Thioredoxin-interacting protein (TXNIP), also known as Vitamin-D upregulated protein-1 (VDUP-1), interacts with thioredoxin to regulate redox responses and participates in diverse disorders including metabolic, cardiovascular, inflammatory and malignant diseases. Psoriasis is characterized by chronic skin inflammation and an aberrant pattern of keratinocyte differentiation. Clinically, psoriasis is associated with various cardiometabolic comorbidities but studies on TXNIP's biological role in skin disorders are limited. In this study, we investigated TXNIP expression in psoriasis and its regulation in normal human epidermal keratinocytes (NHEKs), and then explored how TXNIP regulated skin keratinocyte differentiation to determine its role in psoriasis pathogenesis. Our immunohistochemical study demonstrated extensive TXNIP expression in the upper and lower epidermis of psoriasis compared to predominant TXNIP expression in the basal layer of normal skin. 1, 25-dihydroxyvitamin D3 suppressed but TGF-α and EGF enhanced TXNIP expression in NHEKs. An inducer of keratinocyte differentiation, phorbol 12-myristate 13-acetate (PMA), also diminished TXNIP expression, which was reversed by PKC-δ knockdown. TXNIP knockdown reduced PMA-induced involucrin and transglutaminse-1 expression, and increased p63 expression in NHEKs but did not significantly affect cell proliferation. H2 O2 -induced ROS production and EGFR phosphorylation decreased in NHEKs with TXNIP knockdown. Furthermore, PMA-induced PKC-δ phosphorylation, TGF-α, and EGF-triggered EGFR phosphorylation were attenuated by TXNIP knockdown. Our results unraveled the regulation and function of TXNIP expression in skin keratinocytes and the cross-regulation between TXNIP and EGFR signaling. These findings imply a role of TXNIP in psoriasis and provide insight into the possible impact of TXNIP regulators on the skin or psoriasis.

Evidence for Lysosomal Dysfunction within the Epidermis in Psoriasis and Atopic Dermatitis

Atopic dermatitis and psoriasis are frequent chronic inflammatory skin diseases. Autophagy plays a substantial role in the homeostasis of an organism. Loss or impairment of autophagy is associated with multiple diseases. To investigate the possibility that autophagy plays a role in atopic dermatitis and psoriasis, we investigated the levels of key ATG proteins in human skin specimens as well as in primary human epidermal keratinocytes exposed to inflammatory stimuli invitro. Although TNF-α facilitated the induction of autophagy in an initial phase, it reduced the levels and enzymatic activities of lysosomal cathepsins in later time periods, resulting in autophagy inhibition. Therefore, TNF-α appears to play a dual role in the regulation of autophagy. The relevance of these invitro findings was supported by the observation that the protein levels of cathepsins D and L are decreased in both psoriasis and atopic dermatitis skin specimens. Taken together, this study suggests that TNF-α blocks autophagy in keratinocytes after long-term exposure, a mechanism that may contribute to the chronicity of inflammatory diseases of the skin and, perhaps, of other organs.

Therapeutic wavelengths of ultraviolet B radiation activate apoptotic, circadian rhythm, redox signalling and key canonical pathways in psoriatic epidermis

Ultraviolet B radiation (UVB) exerts pleiotropic effects on human skin. DNA damage response and repair pathways are activated by UVB; if damage cannot be repaired, apoptosis ensues. Although cumulative UVB exposure predisposes to skin cancer, UVB phototherapy is widely used as an effective treatment for psoriasis. Previous studies defined the therapeutic action spectrum of UVB and showed that psoriasis is resistant to apoptosis. This study aimed to investigate early molecular responses within psoriasis plaques following irradiation with single equi-erythemogenic doses of clinically-effective (311 nm, narrow-band) compared to clinically-ineffective (290 nm) UVB. Forty-eight micro-dissected epidermal samples from 20 psoriatic patients were analyzed using microarrays. Our bioinformatic analysis compared gene expression between 311 nm irradiated, 290 nm irradiated and control psoriasis epidermis to specifically identify 311 nm UVB differentially expressed genes (DEGs) and their upstream regulatory pathways. Key DEGs and pathways were validated by immunohistochemical analysis.There was a dynamic induction and repression of 311 nm UVB DEGs between 6 h and 18 h, only a limited number of DEGs maintained their designated expression status between time-points. Key disease and function pathways included apoptosis, cell death, cell migration and leucocyte chemotaxis. DNA damage response pathways, NRF2-mediated oxidative stress response and P53 signalling were key nodes, interconnecting apoptosis and cell cycle arrest. Interferon signalling, dendritic cell maturation, granulocyte adhesion and atherosclerotic pathways were also differentially regulated. Consistent with these findings, top transcriptional regulators of 311 nm UVB DEGs related to: a) apoptosis, DNA damage response and cell cycle control; b) innate/acquired immune regulation and inflammation; c) hypoxia/redox response and angiogenesis; d) circadian rhythmicity; f) EGR/AP1 signalling and keratinocyte differentiation; and g) mitochondrial biogenesis.This research provides important insights into the molecular targets of 311 nm UVB, underscoring key roles for apoptosis and cell death. These and the other key pathways delineated may be central to the therapeutic effects of 311 nm in psoriasis.

Potential Role of Cytosolic RNA Sensor MDA5 as an Inhibitor for Keratinocyte Differentiation in the Pathogenesis of Psoriasis.

BackgroundPsoriasis is a chronic inflammatory skin disease. The etiology of psoriasis is not fully understood, but the genetic background is considered to be the most important factor. To date, many psoriasis-related genes have been discovered, but the role of many important genes has not been well understood.ObjectiveThe purpose of this study is to uncover possible roles of MDA5 in psoriasis.MethodsExpression of MDA5 was investigated using immunohistochemistry. Then, MDA5 was overexpressed in keratinocytes using a recombinant adenovirus.ResultsAs a result of immunohistochemical staining, the expression of MDA5 was significantly increased in the epidermis of psoriasis compared to normal skin. Similarly, the expression of MDA5 was increased in imiquimod-induced psoriasiform dermatitis model. In cultured keratinocytes, toll-like receptor 3 agonist poly(I:C) induced expression of MDA5 at both mRNA and protein levels. When MDA5 was overexpressed using a recombinant adenovirus, poly(I:C)-induced cytokine expression was significantly increased. Finally, MDA5 overexpression significantly inhibited calcium-induced differentiation of keratinocytes.ConclusionThese results suggest that MDA5 increases in psoriasis and negatively regulates keratinocyte differentiation.

The Use of Stem Cell Differentiation Stage Factors (SCDSFs) Taken from Zebrafish Embryos during Organogenesis and Their Role in Regulating the Gene Expression of Normal and Pathological (Stem) Cells.

Studies conducted on Zebrafish embryos in our laboratory have allowed for the identification of precise moments of organogenesis in which a lot of genes are switched on and off, a sign that the genome is undergoing substantial changes in gene expression. Stem cell growth and differentiation stage-factors present in different moments of organogenesis have proven to have different specific functions in gene regulation. The substances present in the first stages of cell differentiation in Zebrafish embryos have demonstrated an ability to counteract the senescence of stem cells, reducing the expression of the beta-galactosidase marker, enhancing the genes Oct-4, Sox-2, c-Myc, TERT, and the transcription of Bmi-1, which act as key telomerase-independent repressors of cell aging. The molecules present in the intermediate to late stages of cell differentiation have proven to be able to reprogram pathological human cells, such as cancer cells and those of the basal layer of the epidermis in psoriasis, which present a higher multiplication rate than normal cells. The factors present in all the stages of cell differentiation are able to counteract neurodegeneration, and to regenerate tissues: It has been possible to regenerate hair follicles in many patients with androgenetic alopecia through transdermal administration of stem cell differentiation stage factors (SCDSFs) by means of cryopass-laser.

325 E3 ligase Trim21 ubiquitylates NF-κB p65 subunit and promotes inflammation in psoriatic keratinocytes

Skin inflammation, a hallmark of psoriasis, has been the focus of study for many years. Tripartite motif-containing protein 21 (Trim21), which is an E3 ligase, is involved in mediating the inflammatory process and participates in the pathogenesis of various autoimmune diseases. We previously noticed that the expression of Trim21, which showed a significant 2. 6 ±0. 5 fold increase in mRNA level as well as an almost 3-fold increase in protein level (p<0. 05) in psoriasis epidermis as compared with normal skin, was markedly upregulated in psoriatic epidermis. Moreover, we proved that Trim21 was the main E3 ligase responsible for the ubiquitination of a marker of hyperproliferation-Keratin 17, which regulated its stability and its interaction with STAT3 in psoriatic keratinocytes. However, its role in mediating the inflammation, especially in keratinocytes, has not been elucidated. Herein, we illustrated a previously unrecognized role for Trim21 in promoting inflammation in keratinocytes, represented by stimulating the release of psoriasis-related cytokines and chemokines CXCL9-11, CCL20, IL-23 and IFN-γ. By screening a myriad of inflammation-related signaling pathways, we clarified that knockdown of Trim21 inhibited the activation of NF-κB and STAT3 pathways. Importantly, by immunoprecipitation combined with in vitro ubiquitination assays, we found that Trim21 interacted with and ubiquitylated p65 subunit of NF-κB, which further enhanced p65 phosphorylation and activation by IKK, initiating expression of the aforementioned downstream cytokines and chemokines. Lastly, in vivo studies showed that knockdown of Trim21 had a satisfactory effect in alleviating the imiquimod (IMQ)-induced psoriasiform lesions. Our present study uncovers a pivotal role of Trim21 in promoting inflammation in psoriatic keratinocytes, which might contribute to the pathogenesis of psoriasis. Thus, Trim21 might be a potential target for the treatment of psoriasis.

Significance of IL-17A-producing CD8+CD103+ skin resident memory T cells in psoriasis lesion and their possible relationship to clinical course

BackgroundA number of studies have shown the relationship between the pathogenesis of psoriasis and skin resident memory T (TRM) cells. ObjectiveTo investigate the cytokine profile of TRM cells from skin lesions of psoriasis and the relationship of skin TRM cells to the future clinical course of psoriasis. MethodsWe used stocked samples of T cells that were ex vivo expanded from skin biopsies of 10 patients with psoriasis vulgaris. A half of 4-mm punch biopsy specimens was subjected to expansion of skin-infiltrating T cells using IL-2 and anti-CD3/CD28 antibody-coated microbeads. More than 106 T cells per specimen were stocked at −80°C. Defrosted cells were subjected to flow cytometric analysis. Another half of skin biopsies were subjected to immmunofluorescence staining for CD103 and other markers. ResultsThe biopsied skin revealed CD8+CD103+ TRM cells were present in the epidermis of psoriasis and associated with acanthosis. Sorted CD103+ T cells were mostly CD8+ memory T cells expressing CD69 with a skin-homing potential. A part of CD8+CD103+ T cells produced interferon-γ, IL-17A or IL-22. Notably, CD8+CD103+ TRM cells more frequently produced IL-17A than did CD8+CD103− T cells. We retrospectively divided the 10 cases into the non-advanced therapy group, and the advanced therapy group in which systemic biologics or others were initiated within one year. The frequency of CD8+CD103+IL-17A+ TRM cells tended to be higher in the advanced therapy group. ConclusionThese results suggest that IL-17A-producing CD8+CD103+ TRM cells are associated with a progressive clinical course of psoriasis.

622 Immature progenitor cells are enriched in psoriasis epidermis

622 Immature progenitor cells are enriched in psoriasis epidermis

309 A novel adipokine C1q/TNF-related proteins-3 decreases in psoriasis patients and ameliorates imiquimod-induced psoriasis-like skin lesions by inhibiting the proliferation and inflammatory cytokines expression of keratinocytes

Latest epidemiological investigations suggest patients with psoriasis have an increased risk of developing metabolic consequences. C1q/TNF-related proteins-3 (CTRP3) is an important newly identified adipokine as a cardio-protective factor and regulator of glucose homeostasis which is mainly produced by mature adipocytes. Here we demonstrated that CTRP3 could regulate imiquimod-induced psoriasis-like skin inflammation. Balb/c mice treated with recombinant mouse CTRP3 showed alleviative disease phenotype and decreased epidermis thickness compared with non-CTRP3 treated psoriatic mice. QRT-PCR assay indicated that the secretion of IL-17A, IL-8, and CXCL1 were decreased in keratinocyte isolated from CTRP3 treated mice. Then we cultured human keratinocyte HaCaT cells and added IFN-γ, TNF-α, IL-17A and IL-22 to simulate the inflammatory environment of psoriasis epidermis in vitro. We found CTRP3 could inhibit the proliferation of HaCaT cells by clone formation method and Ki67 mRNA expression. The inflammatory cytokines and chemokines were also down regulated in the CTRP3-protective group compared with compound cytokines cells. Moreover, we found serum levels of CTRP3 in patients of psoriasis vulgaris were significantly lower compared with age and sex matched healthy controls. Additionally, CTRP3 levels were reduced in moderate-to-server psoriasis patients and alcoholic individuals. We further detected CTRP3 levels of patients were rescued after systemic treatment in the in-patient department. Finally, we discovered the expression of CTRP3 during pre-adipocyte differentiation and maturation could be supressed by TNF-α not IL-17A nor IL-22. In summary, our findings demonstrated the possible therapeutically effect of CTRP3 in the pathogenesis of psoriasis which would imply a mechanism underlying relationship between psoriasis and metabolic and cardiovascular disorders.

Overexpression of Psoriasin (S100A7) Contributes to Dysregulated Differentiation in Psoriasis.

Psoriasin, which is highly expressed in psoriasis, is encoded by a gene located within the epidermal differentiation complex. The aim of this study was to investigate the effect of endogenous psoriasin on disturbed keratinocyte differentiation in psoriasis. Immunohistochemical staining revealed a gradient of psoriasin expression in the psoriatic epidermis with highest expression in the suprabasal, differentiated layers. Induction of keratinocyte differentiation caused concurrent expression of psoriasin and the differentiation marker involucrin. The differentiation-induced psoriasin expression was found to be mediated by the protein kinase C pathway. The downregulation of psoriasin expression by small interfering RNA revealed that psoriasin mediates the expression of involucrin, desmoglein 1, transglutaminase 1 and CD24 in normal differentiation. The lentivirus-mediated overexpression of psoriasin, mimicking the psoriatic milieu, gave rise to an altered regulation of differentiation genes and an expression pattern reminiscent of that in psoriatic epidermis. These findings suggest that psoriasin contributes to the dysregulated differentiation process in the psoriasis epidermis.

Programmed death-ligand 1,2 expressions are decreased in the epidermis of psoriasis

Programmed death-ligand 1,2 expressions are decreased in the epidermis of psoriasis

Activation of p38 MAPK mediates the induction of murine psoriatic dermatitis

Psoriasis is considered to be a Th17 type skin disorder. However, the trigger of Th17 response remains unknown. We previously reported that keratinocyte-specific double knockout of NF-kappaB isoforms developed psoriatic dermatitis. A lack of negative feedback pathway in NF-kappaB cascades is expected to lead to hyperactivation of other subordinate pathways in the epidermis and the development of psoriasis. One of the candidates is p38 mitogen activated protein kinase (MAPK) that shares the upper molecules in its signaling pathway with NF-kappaB and is activated in the epidermis in psoriasis. Nevertheless, the role of p38 in pathogenesis of psoriasis remains unexplored. Here, we report that daily topical application with a p38 activator, anisomycin, induces scaly erythema, epidermal thickening, dermal edema, and infiltration of leukocytes into the dermis and the cornified layer of the murine skin, which are similar to the clinical and histological findings of human psoriasis. The thickness of the treated ears was significantly increased by anisomycin treatment in a dose-dependent manner. The lesional gene expression levels of IL-24, IL-23p19, IL-22, and IL-17a, which are involved in the Th17 response, were markedly increased. The number of IL-17a-producing gamma delta T cells and neutrophils infiltrating into the skin was increased in the anisomycin-treated sites. Concordantly, all these responses were prevented by simultaneous treatment with BIRB 796, a kinase inhibitor specific to p38alpha. These results suggest that activation of p38 is sufficient to induce psoriatic dermatitis in mice, and that psoriasis is developed by the breakdown of skin homeostasis. This new animal model provides us a useful tool to explore a primary trigger of Th17 response in psoriasis.

Neutrophil extracellular trap formation is increased in psoriasis and induces human β-defensin-2 production in epidermal keratinocytes.

Neutrophil extracellular traps (NETs) have been implicated in the development of certain immune-mediated diseases, but their role in psoriasis has not been clearly defined. Human β-defensin-2 (HBD-2) is an important antimicrobial peptide overexpressed in psoriasis epidermis. We evaluated whether the amount of NETs is increased in psoriasis and determined the effect of NETs on HBD-2 production in epidermal keratinocytes. Using fluorescent microscopy, we found that patients with psoriasis (n = 48) had higher amount of NETotic cells in their peripheral blood compared to healthy controls (n = 48) and patients with eczema (n = 35). Psoriasis sera showed increased ability to induce NET formation in control neutrophils but normal NET degradation ability. The amount of NETs in the peripheral blood correlated with psoriasis disease severity. NETosis was also observed in the majority (18 of 20) of psoriasis skin specimens. Furthermore, NETs induced HBD-2 mRNA and protein production in keratinocytes, and immunohistochemical analysis confirmed strong expression of HBD-2 in psoriasis lesional skin. In summary, NET formation is increased in peripheral blood and lesional skin of psoriasis patients and correlates with disease severity. Additionally, NET-induced HBD-2 production may provide a novel mechanism for the decreased susceptibility of psoriasis plaques to microbial infections.

NF-κB-induced microRNA-31 promotes epidermal hyperplasia by repressing protein phosphatase 6 in psoriasis.

NF-κB is constitutively activated in psoriatic epidermis. However, how activated NF-κB promotes keratinocyte hyperproliferation in psoriasis is largely unknown. Here we report that the NF-κB activation triggered by inflammatory cytokines induces the transcription of microRNA (miRNA) miR-31, one of the most dynamic miRNAs identified in the skin of psoriatic patients and mouse models. The genetic deficiency of miR-31 in keratinocytes inhibits their hyperproliferation, decreases acanthosis and reduces the disease severity in psoriasis mouse models. Furthermore, protein phosphatase 6 (ppp6c), a negative regulator that restricts the G1 to S phase progression, is diminished in human psoriatic epidermis and is directly targeted by miR-31. The inhibition of ppp6c is functionally important for miR-31-mediated biological effects. Moreover, NF-κB activation inhibits ppp6c expression directly through the induction of miR-31, and enhances keratinocyte proliferation. Thus, our data identify NF-κB-induced miR-31 and its target, ppp6c, as critical factors for the hyperproliferation of epidermis in psoriasis.

The localization of cyclic nucleotides in the human epidermis: an immunohistochemical study.

Immunohistochemical localizations of 3',5'-cyclic AMP (cAMP) and 3',5'-cyclic GMP (cGMP) were performed in the involved and non-involved epidermis of psoriasis and in the normal controls. The following results were obtained: 1. In the normal epidermis, cAMP was located in the cytoplasm throughout the epidermis but it was more pronounced in its upper portions, especially in the granular layers. Occasionally it was also observed in the nuclear membrane. However, cGMP was located mainly in the cytoplasm of the lower layers of epidermis, though the fluorescence was less pronounced as compared with that of cAmP. 2. In the noninvolved psoriatic epidermis, the localization pattern of cAMP was basically similar to that in the normal control, but its fluorescence seemed more pronounced. The fluorescence of cGMP was essentially the same as that in the normal control. 3. In the involved psoriatic epidermis, the distribution pattern of cAMP was essentially the same as that in the normal control, but its fluorescence seemed more pronounced. Marked increase in the fluorescence of cGMP was observed in the involved psoriatic epidermis, though it was much more pronounced in its lower portions.