Role In Pathogenesis Of Psoriasis Research Articles

Immunohistochemical Assessment of Phosphodiesterase 4A and Phosphodiesterase 4D in Relation to Serum Levels of Phosphodiesterase 4 in Patients with Chronic Plaque Psoriasis

Abstract Psoriasis is an immune-mediated genetic skin disease. The underlying pathomechanisms involve complex interaction between the innate and adaptive immune system. T-cells interact with dendritic cells, macrophages, and keratinocytes, which can be mediated by their secreted cytokines. Dysregulation of the immune response is thought to result in a chronic imbalance in the production of pro-inflammatory and anti-inflammatory cytokines. Phosphodiesterase (PDE4) act as proinflammatory enzymes via degradation of cAMP, whereas PDE4 inhibitors play an anti-inflammatory role in vitro and in vivo. In particular, topical and systemic PDE4 inhibitor has been approved for the treatment of psoriasis and psoriatic arthritis. However, little is known on the expression pattern of PDE4 in psoriasis. We report that serum PDE4 are overexpressed in blood of patients with chronic plaque psoriasis, as compared with normal controls. PDE4 expression is up-regulated in psoriatic dermis as compared with normal skin, with particular regard to dermal lymphocytes. Taken together, these results indicate that PDE4 play an important role in psoriasis pathogenesis and supports promises put on topical PDE4 inhibitors in treatment of psoriasis.

Effects of secukinumab combined with tretinoin on metabolism, liver enzymes, and inflammatory factors in patients with moderate to severe psoriasis vulgaris.

Psoriasis is a T cell-mediated polygenic chronic inflammatory disease. Interleukin (IL)-17A plays a major role in psoriasis pathogenesis. Secukinumab is a high-affinity human monoclonal antibody against IL-17A. This article explored efficacy and safety of secukinumab plus tretinoin in moderate to severe psoriasis (MSP) vulgaris, and assessed metabolism, liver function, and inflammation. A total of 135 patients diagnosed with moderate or severe psoriasis vulgaris were enrolled and randomized into three groups at a 1 : 1 : 1 ratio, receiving treatment with rretinoin, secukinumab, or combination therapy for a duration of 16 weeks. Psoriasis area and severity index (PASI) scores, serum T lymphocyte subsets, glucose, lipid, and uric acid (UA) metabolism, liver enzymes, and inflammatory factors (IFs) were measured. Following the therapy, subjects had decreased PASI scores, increased serum CD3+, CD4+, and CD4+/CD8+, decreased serum CD8+, and decreased serum UA and IL-2, IL-6, IL-23, interferon-γ (IFN-γ), and tumor necrosis factor (TNF)-α (p < 0.05). Total cholesterol, triglycerides, low-density lipoprotein, high-density lipoprotein, apolipoproteins A1, B, fasting blood glucose, alanine transaminase, aspartate transaminase, and alkaline phosphatase had no obvious differences among the subjects (p > 0.05). As against the Tretinoin and the Secukinumab groups, the PASI score was visiblysmaller, the changes in serum T lymphocyte subsets were more obvious, and serum UA and IFs were lower in the Combination group following the therapy (p < 0.05). Secukinumab combined with tretinoin is more effective in MSP vulgaris, which can visibly reduce inflammatory response without affecting glucose and lipid metabolism and liver function.

Interleukin 17A-correlated myocarditis in patients with psoriasis: cardiac recovery following secukinumab administration

Abstract Background Psoriasis (PS) is a common immune-mediated disease of the skin with possible extension to joints, aorta and eye. Myocardial inflammation has been rarely suggested. Purpose Report of PS-related myocarditis. Methods One hundred consecutive patients with PS were screened for cardiac involvement. Among them, five male patients (aged 56 ± 9.5 years) with moderate-severe form showed a dilated cardiomyopathy (LVEF &amp;lt;35%) with normal coronary arteries and valves. They underwent a left ventricular endomyocardial biopsy for evaluation of myocardial substrate. Endomyocardial samples were processed for histology and immunohistochemistry, including myocardial expression of Toll-Like Receptor 4 (TLR4) and interleukin-17A (IL-17A), which plays a major role in psoriasis pathogenesis; real-time PCR for cardiotropic viruses and Western blot analysis for myocardial expression of IL-17A. Patients’ sera were tested for anti-heart autoantibodies. Results An active lymphocytic myocarditis was revealed in all 5 patients, characterized by absence of viral genomes at PCR, positive anti-heart autoantibodies, overexpression of TLR-4 and enhancement of IL-17-A at western blot analysis showing a 2,48-fold increase in psoriatic myocarditis compared with no psoriatic myocarditis and a 6-fold increase compared to myocardial controls. Treatment included combination of prednisone (1 mg/Kg daily for 4 weeks, tapered to 0.33 mg/Kg) + azathioprine (2 mg/Kg, daily) in 3 pts or secukinumab (SK, 100 mg/monthly) in 2 pts for 6 months. LVEDD and LVEF improved in the first 3 pts (-14% and + 118%, respectively) while completely recovered (LVEF&amp;gt; 50%) in the last 2 pts on SK. Conclusion IL-17A-related myocarditis can occur in up-to 5% of patients with psoriasis. It manifests as a progressive dilated cardiomyopathy. It may completely recover following SK administration. Figure Legend Endomyocardial biopsy findings from pt 5 with PS-related myocarditis including histology (panel A). Immune-histochemistry for IL 17-A (panel B) and anti-heart abs (panels C, D). It shows an active lymphocytic myocarditis with overexpression of IL 17-A and positive anti-heart abs (panel C), cross-reacting with skeletal muscle (panel D).

Exploring the molecular mechanism underlying the psoriasis and T2D by using microarray data analysis

Although a large number of evidence has identified that psoriasis is significantly correlated with type 2 diabetes (T2D), the common molecular mechanism of its occurrence remains unclear. Our study aims to further elucidate the mechanism of the occurrence of this complication. We obtained the gene expression data of psoriasis (GSE30999) and T2D (GSE28829) from the Gene Expression Omnibus (GEO) dataset. Then the common differentially expressed genes (DEGs) of T2D and psoriasis were identified. After that, we performed three types of analyses about these DEGs, including functional enrichment analysis, protein–protein interaction (PPI) network and module manufacture, hub genes identification and co-expression analysis. 132 common DEGs (14 upregulated genes and 118 downregulated genes) were identified for subsequent a series of analyses. Function enrichment analysis demonstrated that Rap1 signaling pathway, PI3K-Akt signaling pathway, and cGMP-PKG signaling pathway may play a significant role in pathogenesis of psoriasis and T2D. Finally, 3 important hub genes were selected by utilizing cytoHubba, including SNRPN, GNAS, IGF2. Our work reveals the potential common signaling pathways of psoriasis and T2D. These Hub genes and common signaling pathways provide insights for further investigation of molecular mechanism about psoriasis and T2D.

Alleviating psoriatic skin inflammation through augmentation of Treg cells via CTLA-4 signaling peptide.

Psoriasis is a chronic inflammatory skin disease characterized by hyperplasia of keratinocytes and immune cell infiltration. The IL-17-producing T cells play a key role in psoriasis pathogenesis, while regulatory T (Treg) cells are diminished during psoriatic inflammation. Current psoriasis treatments largely focus on IL-17 and IL-23, however, few studies have explored therapeutic drugs targeting an increase of Treg cells to control immune homeostasis. In this study, we investigated the effects of a cytotoxic T lymphocyte antigen-4 (CTLA-4) signaling peptide (dNP2-ctCTLA-4) in Th17, Tc17, γδ T cells, Treg cells in vitro and a mouse model of psoriasis. Treatment with dNP2-ctCTLA-4 peptide showed a significant reduction of psoriatic skin inflammation with increased Treg cell proportion and reduced IL-17 production by T cells, indicating a potential role in modulating psoriatic skin disease. We compared dNP2-ctCTLA-4 with CTLA-4-Ig and found that only dNP2-ctCTLA-4 ameliorated the psoriasis progression, with increased Treg cells and inhibited IL-17 production from γδ T cells. In vitro experiments using a T cell-antigen presenting cell co-culture system demonstrated the distinct mechanisms of dNP2-ctCTLA-4 compared to CTLA-4-Ig in the induction of Treg cells. These findings highlight the therapeutic potential of dNP2-ctCTLA-4 peptide in psoriasis by augmenting Treg/Teff ratio, offering a new approach to modulating the disease.

Interleukin-17A-Correlated Myocarditis in Patients with Psoriasis: Cardiac Recovery following Secukinumab Administration.

(1) Background: Psoriasis (PS) is a common immune-mediated disease of the skin with possible extension to joints, aorta and eye. Myocardial inflammation has rarely been suggested. (2) Aims: Report of PS-related myocarditis. (3) Methods and Results: One hundred consecutive patients with PS were screened for cardiac involvement. Among them, five male patients (aged 56 ± 9.5 years) with a moderate-severe form of PS showed dilated cardiomyopathy (LVEF < 35%) with normal coronary arteries and valves. They underwent a left-ventricular endomyocardial biopsy for evaluation of myocardial substrate. Endomyocardial samples were processed for histology and immunohistochemistry, including myocardial expression of Toll-Like Receptor 4 (TLR4) and interleukin-17A (IL-17A), which play a major role in PS pathogenesis. Real-time PCRs were carried out for cardiotropic viruses, and Western blot analysis was conducted for myocardial expression of IL-17A. Patients' sera were tested for anti-heart autoantibodies. Active lymphocytic myocarditis was revealed in all five patients, characterized by an absence of viral genomes with PCR, positive anti-heart autoantibodies, overexpression of TLR-4 and enhancement of IL-17-A during western blot analysis, showing a 2.48-fold increase in psoriatic myocarditis compared with no psoriatic myocarditis and a six-fold increase compared to myocardial controls. Treatment included combination of prednisone (1 mg/kg daily for 4 weeks, tapered to 0.33 mg/kg) and azathioprine (2 mg/kg, daily) in 3 pts or secukinumab (SK, 150 mg/weekly for 4 weeks followed by 150 mg/monthly) in 2 pts for 6 months. LVEDD and LVEF improved in the first 3 pts (-14% and + 118%, respectively), while they completely recovered (LVEF > 50%) in the last 2 pts on SK. (4) Conclusions: IL-17A-related myocarditis can occur in up to 5% of patients with PS. It manifests as progressive dilated cardiomyopathy. It may completely recover following SK administration.

BCL11B Is Involved in Stress-Induced Differentiation of Keratinocytes and Has A Potential Role in Psoriasis Pathogenesis.

Psoriasis is a common, auto-immune skin disease characterized by abnormal proliferation and differentiation of keratinocytes. Studies revealed the role of stress stimulators in the pathogenesis of psoriasis. Oxidative stress and heat shock are two important stress factors tuning differentiation and proliferation of keratinocytes, regarding to psoriasis disease. BCL11B is a transcription factor with critical role in embryonic keratinocyte differentiation and proliferation. Given this, in keratinocytes we have investigated potential role of BCL11B in stress-induced differentiation. Furthermore, we searched for a potential intercommunication between BCL11B expression and psoriasis-related keratinocyte stress factors. In this experimental study, data sets of psoriatic and healthy skin samples were downloaded in silico and BCL11B was chosen as a potential transcription factor to analyze. Next, a synchronized in vitro model was designed for keratinocyte proliferation and differentiation. Oxidative stress and heat shock treatments were employed on HaCaT keratinocytes in culture, and BCL11B expression level was measured. Cell proliferation rate and differentiation were analyzed by synchronized procedure test. Flow cytometry was done to analyze cell cycle alterations due to the oxidative stress. Quantitative reverse transcription polymerase chain reaction (qRT-PCR) data revealed a significant upregulation of BCL11B expression in keratinocytes, by 24 hours after initiating differentiation. However, it was followed by a significant down-regulation in almost all the experiments, including the synchronized model. Flow cytometer data demonstrated a G1 cell cycle arrest in the treated cells. Results indicated a remarkable role of BCL11B in differentiation and proliferation of HaCaT keratinocytes. This data along with the results of flow cytometer suggested a probable role for BCL11B in stress-induced differentiation, which is similar to what is happening during initiation and progression of normal differentiation.

Study of serum lipid profile in psoriaticpatients and correlation with disease severity

Introduction :Psoriasis is a chronic proliferative skin disorder with reported incidence of 1.5%-4.8% in different countries. Its etiology is still unknown, while genetic, metabolic and immunological mechanisms have been recommended as its causes. Literature suggests that lipid metabolism maybe play a significant a role in pathogenesis of psoriasis, and psoriatic patients manifest significant lipid abnormalities.Patients and Methods: The study comprised 53 psoriatic patients and 50 age and sex matched healthy subject. For all patients, clinical assessment by using Psoriasis Area and Severity Index (PASI) score was performed, and fasting blood sampling was collected to assess the lipid profile.Results: Psoriatic patients, in comparison to healthy subjects, show a significant high serum level of total cholesterol (TCH) and low-density lipoprotein cholesterol (LDL) and no significant differences in the serum level of triglyceride (TG), very low-density lipoprotein cholesterol (VLDL), and high-density lipoprotein cholesterol (HDL). Conclusions: Psoriatic patients were associated with lipid abnormalities. Atorvastatin shows a promise role in treatment of psoriasis. Furthermore, Atorvastatin demonstrate a beneficial therapeutic role in psoriasis by its hypolipemic efficacy. Further studies were recommended to assess the therapeutic efficacy of lipid lowering drugs in treatment of psoriasis

Soluble adenylyl cyclase contributes to imiquimod-mediated inflammation and is a potential therapeutic target in psoriasis.

Cyclic AMP (cAMP) has a key role in psoriasis pathogenesis, as indicated by the therapeutic efficacy of phosphodiesterase inhibitors that prevent the degradation of cAMP. However, whether soluble adenylate cyclase (sAC) (encoded by the ADCY10 gene), which is an important source for cAMP, is involved in Th17 cell-mediated inflammation or could be an alternative therapeutic target in psoriasis is unknown. We have utilized the imiquimod model of murine psoriasiform dermatitis to address this question. Adcy10-/- mice had reduced erythema, scaling and swelling in the skin and reduced CD4+ IL17+ cell numbers in the draining lymph nodes, compared with wild-type mice after induction of psoriasiform dermatitis with imiquimod. Keratinocyte-specific knock out of Adcy10 had no effect on imiquimod-induced ear swelling suggesting keratinocyte sAC has no role in imiquimod-induced inflammation. During Th17 polarization in vitro, naive T cells from Adcy10-/- mice exhibited reduced IL17 secretion and IL-17+ T-cell proliferation suggesting that differentiation into Th17 cells is suppressed without sAC activity. Interestingly, loss of sAC did not impact the expression of Th17 lineage-defining transcription factors (such as Rorc and cMaf) but rather was required for CREB-dependent gene expression, which is known to support Th17 cell gene expression. Finally, topical application of small molecule sAC inhibitors (sACi) reduced imiquimod-induced psoriasiform dermatitis and Il17 gene expression in the skin. Collectively, these findings demonstrate that sAC is important for psoriasiform dermatitis in mouse skin. sACi may provide an alternative class of topical therapeutics for Th17-mediated skin diseases.

Assessment of the Potential Role of Selected Single Nucleotide Polymorphisms (SNPs) of Genes Related to the Functioning of Regulatory T Cells in the Pathogenesis of Psoriasis

Recent studies have indicated a key role of the impaired suppressive capacity of regulatory T cells (Tregs) in psoriasis (PsO) pathogenesis. However, the genetic background of Treg dysfunctions remains unknown. The aim of this study was to evaluate the association of PsO development with selected single nucleotide polymorphisms (SNPs) of genes in which protein products play a significant role in the regulation of differentiation and function of Tregs. There were three study groups in our research and each consisted of different unrelated patients and controls: 192 PsO patients and 5605 healthy volunteers in the microarray genotyping group, 150 PsO patients and 173 controls in the ARMS-PCR method group, and 6 PsO patients and 6 healthy volunteers in the expression analysis group. The DNA microarrays analysis (283 SNPs of 57 genes) and ARMS-PCR method (8 SNPs in 7 genes) were used to determine the frequency of occurrence of SNPs in selected genes. The mRNA expression of selected genes was determined in skin samples. There were statistically significant differences in the allele frequencies of four SNPs in three genes (TNF, IL12RB2, and IL12B) between early-onset PsO patients and controls. The lowest p-value was observed for rs3093662 (TNF), and the G allele carriers had a 2.73 times higher risk of developing early-onset PsO. Moreover, the study revealed significant differences in the frequency of SNPs and their influence on PsO development between early- and late-onset PsO. Based on the ARMS-PCR method, the association between some polymorphisms of four genes (IL4, IL10, TGFB1, and STAT3) and the risk of developing PsO was noticed. Psoriatic lesions were characterized with a lower mRNA expression of FOXP3, CTLA4, and IL2, and a higher expression of TNF and IL1A in comparison with unaffected skin. In conclusion, the genetic background associated with properly functioning Tregs seems to play a significant role in PsO pathogenesis and could have diagnostic value.

SERPINB4 Promotes Keratinocyte Inflammation via p38MAPK Signaling Pathway.

Psoriasis is a chronic inflammatory skin disease characterized by infiltration of inflammatory cells and excessive proliferation of epidermal keratinocytes. SERPINB4, as a serine protease inhibitor, has been clearly expressed in the skin lesions and serum of patients with psoriasis, but the specific mechanism of action is not yet clear. Here, we showed that SERPINB4 expression was increased in skin lesions from the imiquimod (IMQ)-treated mice and M5-(a mixture of five proinflammatory cytokines: IL-17A, IL-22, IL-1α, oncostatin M, and TNF-α) treated human immortalized keratinocyte (HaCaT). Knockdown of SERPINB4 by short hairpin RNA attenuated the M5-induced keratinocyte inflammation. Conversely, lentiviral expression of SERPINB4 promoted keratinocyte inflammation. Finally, we observed that SERPINB4 stimulation activated the p38MAPK signaling pathway. Taken together, these results suggest that SERPINB4 has a critical role in psoriasis pathogenesis.

343 Endogenous double-stranded RNA is a potential target for psoriasis therapy

The activation of endogenous double-stranded RNA (endo-dsRNA) signalling pathways is linked to a variety of autoimmune diseases. Here, we investigated the role of endogenous dsRNA in psoriasis by quantifying dsRNA binding protein (DRBP) mRNA and mitochondrial dsRNA formation in response to narrow-band UVB (NB-UVB) treatment. RNAseq data from 34 psoriatic patients treated with NB-UVB were analysed. Biopsies were obtained from four sites 24h after NB-UVB irradiation (lesional unirradiated, nonlesional unirradiated lesional irradiated with one minimal erythemal dose (MED), lesional irradiated with three MEDs. Psoriatic lesional skin had a significantly higher expression of all examined DRBP (RIG, MDA5, LGP2, PKR, OAS1-3, OASL) as compared to nonlesional skin (increase between 1.5-21.7 fold, p <0.001 for all eight genes). NB-UVB treatment had no effect on the DRBPs after 24h of one or three MEDs of NB-UVB. Additionally, a significant reduction (about 20%) of dsRNA from mitochondrial transcripts was detected in response to both NB-UVB doses(p-value 0.012 and 0.001, respectively). These results indicate that increased levels of dsRNA activate RIG, MDA5, and LGP2 in lesional compared to nonlesional psoriasis skin. RIG, MDA5, and LGP2 in turn upregulate type1 IFN via recruiting TBK1, and IRF3/7, all of which were significantly upregulated in the lesional unirradiated skin. PKR binds endo-dsRNA, and activation of PKR enhances IFN-α/β expression via IRF3. Moreover, OASs trigger an antiviral response via a RIG induced IFN pathway. Once activated, IFN strongly enhances the transcription of DRBP thus creating a vicious cycle that exacerbates the immune response. In conclusion, upregulation of all DRBP genes in psoriatic lesional skin indicates that endo-dsRNA may play a crucial role in psoriasis pathogenesis, and the early reduction of the mitochondrial dsRNA after NB-UVB treatment suggests that dsRNA is an important target for psoriasis therapy.

Abstract 10450: Interleukin-17A-Correlated Myocarditis in Patients With Psoriasis

Background. Psoriasis is a common immune-mediated disease of the skin with possible extension to joints, aorta and eye. Myocardial inflammation has been rarely suggested. However, its incidence and pathologic mechanism have not been elucidated so far. Methods. One hundred consecutive patients (62M/38F, mean age 55 ± 13.7 years) with psoriasis were screened for cardiac involvement. Among them, five male patients (mean age 56 ± 9.5 years) showed a dilated cardiomyopathy (LVEF &lt; 40%) with normal coronary arteries and valves, and underwent a left ventricular endomyocardial biopsy for evaluation of myocardial substrate. Endomyocardial samples were processed for histology and immunohistochemistry, including myocardial expression of Toll-Like Receptor 4 (TLR4) and interleukin-17A (IL-17A), which plays a major role in psoriasis pathogenesis. Real-time PCR for cardiotropic viruses and Western blot analysis for myocardial expression of IL-17A were also performed. As controls for IL-17A expression, myocardial samples from 10 male patients with inflammatory cardiomyopathy and no psoriasis were included. Patients’ sera were tested for anti-heart autoantibodies. Results. An active lymphocytic myocarditis was revealed in all 5 patients, characterized by absence of viral genomes at PCR, positive anti-heart autoantibodies, overexpression of TLR-4 and of IL-17A at both immunohistochemistry (Figure 1A vs 1B) and Western blot analysis (mean value 44 ± 6.7 vs 12 ± 61.9 in patients with no-psoriatic myocarditis and 4± 1.5 in normal controls; Figure 1C). Conclusion. Interleukin-17A-related myocarditis can occur in up-to 5% of patients with psoriasis. It manifests as a progressive dilated cardiomyopathy that can potentially benefit from immunosuppression or monoclonal antibodies as the skin disease.

Chemokine Profile in Psoriasis Patients in Correlation with Disease Severity and Pruritus.

Psoriasis (PsO) is a chronic, immune-mediated, inflammatory skin disease associated in most cases with pruritus. Chemokines seem to play a significant role in PsO pathogenesis. The aim of the study was to analyse serum concentrations of CCL2/MCP-1, CCL3/MIP-1α, CCL4/MIP-1β, CCL5/RANTES, CCL17/TARC, CCL18/PARC, CCL22/MDC and CXCL8/IL-8, and their correlation with PsO severity and pruritus intensity. The study included 60 PsO patients and 40 healthy volunteers. Serum concentrations of six (CCL2/MCP-1, CCL3/MIP-1α, CCL5/RANTES, CCL17/TARC, CCL18/PARC and CCL22/MDC) out of eight analysed chemokines were significantly elevated in PsO patients; however, they did not correlate with disease severity. The serum level of CCL5/RANTES was significantly higher in patients with the psoriasis area and severity index (PASI) ≥ 15 (p = 0.01). The serum concentration of CCL17/TARC correlated positively with pruritus assessed using the visual analogue scale (VAS) (R = 0.47; p = 0.05). The study indicated CCL17/TARC as a potential biomarker of pruritus intensity in PsO patients. Chemokines appear to be involved in the development of PsO systemic inflammation. Further detailed studies on the interactions between chemokines, proinflammatory cytokines and immune system cells in PsO are required to search for new targeted therapies.

Circulating microRNA203 and its target genes' role in psoriasis pathogenesis.

Numerous microRNAs (miRNAs) have been found to have an aberrant expression in the peripheral blood or psoriasis patients' lesions. Psoriasis was shown to have the abnormal expression of microRNA-203 (miR-203). It is a skin-specific signal that governs cellular proliferation in a protein kinase C-dependent manner and is mostly generated by keratinocytes. This work evaluated the expression levels of the circulating miR-203 target genes SOCS3, SOCS6, TP63, TNF-, IL8, and IL24 in psoriasis patients. Using a relative quantitation PCR technique, we determined the expression levels of miR-203 and its target genes (SOCS3, SOCS6, TP63, TNF-, IL8, and IL24) in the plasma of 120 psoriatic patients and matched healthy controls. The disease characteristics of the patients were then correlated with the expression results. We also conducted numerous enrichment analyses for the diseases, functions, and pathways connected to the under-researched biomarkers. Compared to healthy controls, psoriatic patients had significantly increased levels of miR-203 expression; 7.1 (4.4-9.9). In contrast, psoriatic patients had significantly lower expression of all the examined genes compared to healthy controls. Regarding all the study biomarkers, the receiver operating characteristic (ROC) curve analysis demonstrated significant sensitivity and specificity for differentiating between psoriatic patients and healthy controls. According to the results of the disease matching score generated by miR-203 and its target genes, psoriasis was ranked first with a score of 4.45. The third-place finisher with a value of 3.98, it also demonstrated that miR-203 and its target genes are connected to various skin disorders. Our results show that miR-203 contributes to psoriasis pathogenesis not only locally in skin lesions but also in circulation, indicating that it may contribute to the systemic symptoms of the illness. MiR-203 overexpression in psoriasis suggests that miR-203 may be involved in an anti-inflammatory response because it targets both SOCS gene family members and pro-inflammatory cytokines.

Changes in mononuclear cell subsets in capillary and venous blood of patients with psoriasis depending on the treatment

Topical glucocorticoids are conventionally used to treat psoriasis, but such treatment provides a short-term effect, and may cause various complications during long-term usage. A detailed study of the immunopathogenesis of psoriasis has made it possible to use bioengineered drugs that block the main cytokines. It has been shown that IL-36 plays an important regulatory role in pathogenesis of psoriasis. The aim of the study was to study therapeutic effect of patients with psoriasis using topical glucocorticoid hormone versus IL- 36 receptor antagonist (RAIL-36), with respect to clinical course of psoriasis and the subsets of mononuclear cells in venous and capillary blood taken close to the focus of inflammation. 16 patients with psoriasis (group 1a) received 0.1% mometasone cream for 14 days; 20 patients of group 1b received a gel containing 0.4% recombinant RAIL-36 for 14 days. Control group included 20 healthy adults. Treatment efficacy was assessed by PASI, DISHS and DLQI indices. 19 lymphocyte subsets and 3 monocyte subsets were assessed by four-color staining of whole capillary and venous blood with erythrocyte lysis using BD Biosciences (USA) technologies and reagents. It was shown that both drugs led to a decrease in the severity of the disease at the end of treatment. However, 2 weeks after the end of treatment in group 1a, the disease indexes nearly returned to the initial values. Meanwhile, the reduced index levels persisted 2 weeks later in group 1b. Significant deviations (more pronounced in capillary blood) were revealed for the levels of several leukocyte subsets in the psoriasis patients compared with healthy persons. As a result of treatment, we have revealed some changes in the levels of leukocyte subsets common to the two groups, and special differences for the two treatment options, that were more pronounced in capillary blood samples. Both medical preparations used are suitable for treatment of psoriasis.

Comparison of Serum Zinc and Copper Level in Psoriatic and Non-Psoriatic Individual

Psoriasis is a common chronic inflammatory disease of skin and multiple organs of body. The exact etiology of psoriasis is not yet certain. It is assumed that trace elements may have some role in pathogenesis of psoriasis. They can act as co-enzymes for metabolism and can act as antioxidants against free radicals. Therefore they can participate in epidermal proliferation and inflammatory process of psoriasis. This study aimed to evaluate the relation between psoriasis and trace elements namely zinc and copper. This study was conducted on 40 diagnosed cases of psoriasis and 40 non psoriatic individuals in the department of Dermatology and Venereology in Bangabandhu Sheikh Mujib Medical University, Dhaka. Biochemical analyses of serum copper and zinc were analyzed and compared statistically with cases and healthy controls. Serum zinc level was significantly lower and serum copper level was significantly higher in patient with psoriasis compared to control (p= &lt; 0.001). Individuals with moderate to severe psoriasis had significantly lower zinc levels and significantly higher copper levels than patients with mild psoriasis, according to Psoriasis area and Severity Index Score (p= &lt; 0.05). Correction of serum zinc and copper level could be beneficial for psoriasis patients. Bangladesh Med J. 2021 May; 50(2) : 28-31

011 A new immunocompetent skin model recapitulates molecular features of psoriasis

Psoriasis is a chronic inflammatory skin disease involving interactions between keratinocytes and both the innate and adaptive immune systems. The IL-17/IL-23 axis is described to drive the release of inflammatory and immune factors in keratinocytes (cytokines, antimicrobial peptides, chimiokines), which sit at the heart of an inflammation amplification loop. To this date, there are very few immunocompetent models recapitulating as close as possible psoriatic skin. In this context, the aim of this work was to develop a 3D model of psoriatic lesional skin summarizing biological features of the pathology. As the dialogue between Th17 lymphocytes (LTh17) and keratinocytes plays a central role in psoriasis pathogenesis, a model taking into account these two biological actors was developed. A reconstructed epidermis (RE) was co-cultured with differentiated LTh17. RE morphology as well as proliferation/differentiation imbalance and inflammatory immune response were explored. As it is reported in psoriatic lesions, results showed that IL-17 family cytokines were increased. Histological analysis demonstrated that the psoriatic mimic epidermis exhibited morphological changes. Moreover, mechanisms of proliferation and differentiation appeared profoundly altered while a high keratinocyte inflammatory response characteristic of psoriasis was observed. In conclusion, we have succeeded in designing a 3D in vitro model reproducing molecular alterations of psoriatic skin. The co-culture of the RE with differentiated LTh17 led to a typical inflammatory response in keratinocytes, thus proving the successful communication of the two biological compartments. This physiological relevant model is suitable for the assessment of natural therapeutic molecules dedicated to psoriasis treatment.

S100A8 (rs3806232) gene polymorphism and S100A8 serum level in psoriasis vulgaris patients: A preliminary study.

S100A8single nucleotide polymorphism (SNP) and S100A8 blood level are related to many inflammatory disorders with no available conclusion in psoriasis. The aim of this study was to evaluate the possible role of S100A8 in psoriasis pathogenesis through analyzing its S100A8 (rs3806232) gene polymorphism and S100A8serum level in psoriasis vulgaris patients, in addition to correlate the detected results with severity psoriasis in those patients. This case-control study was conducted on 50 patients having psoriasis vulgaris, and 26 controls. Severity of psoriasis was evaluated using psoriasis area and severity index (PASI) score. S100A8serum level and S100A8 (rs3806232) SNP were evaluated by ELISA and polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) respectively. Serum S100A8level was significantly higher in psoriatic patients than controls and was positively correlated with PASI score (r=0.826, p<0.001). S100A8 (rs3806232) AA genotype and A allele were significantly increased among psoriasis patients than controls (p<0.001) increasing risk of psoriasis development by about 5, 12, and 6 times than AG, GG, and G alleles. AA genotype was significantly associated with psoriasis severity (p=0.005) and high S100A8serum levels (p=0.018). Circulating S100A8 could associated with disease severity and have an active role in psoriasis pathogenesis. S100A8 (rs3806232) SNP (AA genotype and A allele) might contribute to development and severity of psoriasis in the Egyptian population.

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.