Psoriasis Skin Lesions Research Articles

Tape strips detect distinct immune and barrier profiles in atopic dermatitis and psoriasis

Our current understanding of atopic dermatitis (AD) and psoriasis pathophysiology is largely derived from skin biopsy studies that cause scarring and may be impractical in large-scale clinical trials. Although tape strips show promise as a minimally invasive technique in these common diseases, a comprehensive molecular profiling characterizing and differentiating the 2 diseases in tape strips is unavailable. Our aim was to construct a global transcriptome of tape strips from lesional and nonlesional skin of adults with moderate-to-severe AD and psoriasis. A total of 20 tape strips were obtained from lesional and nonlesional skin of patients with AD and psoriasis and skin from controls (n= 20 each); the strips were subjected to RNA sequencing (RNA-seq), with quantitative RT-PCR validation of immune and barrier biomarkers. We detected RNA-seq profiles in 96 of 100 of samples (96%), with 4123 and 5390 genes differentially expressed in AD and psoriasis lesions versus in controls, respectively (fold change≥ 2; false discovery rate [FDR]< 0.05). Nonlesional tape-stripped skin from patients with AD was more similar to lesional skin than to nonlesional skin of patients with psoriasis, which showed larger differentiation from lesions. AD and psoriasis tissues shared increases in levels of dendritic cell and T-cell markers (CD3, ITGAX/CD11c, and CD83), but AD tissues showed preferential TH2 skewing (IL-13, CCL17/TARC, and CCL18), whereas psoriasis was characterized by higher levels of expression of TH17-related (IL-17A/F and IL-36A/IL-36G), TH1-related (IFN-γ and CXCL9/CXCL10), and innate immunity-related (nitric oxide synthase 2/inducible nitric oxide synthase and IL-17C) products (FDR< 0.05). Terminal differentiation (FLG2 and LCE5A), tight junction (CLDN8), and lipid biosynthesis and metabolism (FA2H and ALOXE3) products were significantly downregulated in both AD and psoriasis (FDR< 0.05). Nitric oxide synthase 2/inducible nitric oxide synthase expression (determined by quantitative PCR) differentiated AD and psoriasis with 100% accuracy. RNA-seq tape strip profiling detected distinct immune and barrier signatures in lesional and nonlesional AD and psoriasis skin, suggesting their utility as a minimally invasive alternative to biopsies for detecting disease biomarkers.

300 Using single cell technique to reveal the expression landscape of lncRNAs in psoriasis

Long-noncoding RNAs (lncRNAs) have been shown to regulate epidermal differentiation in skin, and bulk RNA-seq data have illustrated the tissue and cell type specificity for skin-expressing lncRNAs. In this study, we assessed the ability to use single cell RNA-seq (scRNA-seq) obtained from 9 psoriasis lesional skin (PP) and 6 uninvolved skin (PN) samples to characterize the expression profiles for lncRNAs in cell-level resolution. Despite the limitation of scRNA-seq in detecting low-expressing transcripts, we identified 4,785 expressing lncRNAs (using threshold of >=2 reads in at least one cell) in majority of the cells.

234 The association of interleukin-36γ, claudin-1 and claudin-7 in psoriasis

Background: To investigate the expression and determine their association of IL-36γ, claudin-1 and claudin-7 in psoriasis. Methods: This study included 42 patients as psoriasis group with 15 persons as control group. The expression of IL-36γ, claudin-1 and claudin-7 were detected by immunohistochemistry. Results: The expression level of IL-36γ in the psoriasis group was significantly higher than that in the control group(P=0.022). The expression levels of claudin-1 and claudin-7 in the psoriasis group were lower compared to control group (P=0.001, 0.001 for claudin-1 and claudin-7 respectively). The expression level of IL-36γ was negatively correlated with that of claudin-1(r=-0.344, P=0.025) and claudin-7(r=-0.320, P=0.039). Conclusion: The expression of IL-36γ increased in psoriasis skin lesions and it was associated with down-regulation of claudin proteins expression in the lesions.

The impacts of gene polymorphisms on methotrexate in Chinese psoriatic patients.

Methotrexate (MTX) is the first-line treatment for psoriasis in China. The metabolic processes of MTX include various proteins and genes. Previous studies have shown that gene polymorphisms had significant impacts on the efficacy of MTX. However, the influence of gene polymorphisms has not been reported in the Chinese psoriatic patients. The aim of this study was to verify the impacts of candidate genes polymorphisms on the effectiveness of MTX in a Chinese psoriatic population. In this study, we enrolled 259 psoriasis patients from two clinical centres. Each of them received MTX treatment at 7.5-15mg/week for at least 8weeks. Patients were stratified as responders and non-responders according to whether the Psoriasis Area and Severity Index score declined more than 75% (PASI75). According to previous reports, 16 single nucleotide polymorphisms (SNPs) were selected and genotyped for each patient using the Sequenom platform. Fisher's exact test, the chi-square test, Mann-Whitney tests and ANOVA analyses were used for statistical analysis. Among 259 patients, there were 182 males and 77 females, 63 patients with psoriatic arthritis and 196 patients without arthritis phenotype, and the age of all patients ranged from 19 to 70years (49.7±13.6). The baseline PASI value of patients was 13.8±8.5, and 33.2% of patients achieved a PASI75 response after MTX treatment. Patients carrying the ATP-binding cassette subfamily B member 1 gene (ABCB1) rs1045642 TT genotype were associated with more severe psoriasis skin lesion (P=0.032). Furthermore, the ABCB1 rs1045642 TT genotype was found to be more frequent in non-responders (P=0.017), especially in moderate-to-severe patients (P=0.002) and patients without psoriatic arthritis (P=0.026) after MTX treatment. We have demonstrated for the first time that polymorphism of the ABCB1 rs1045642 TT genotype is predictive of a worse clinical response of skin lesions to MTX therapy in a Chinese psoriatic population.

A cascaded deep convolution neural network based CADx system for psoriasis lesion segmentation and severity assessment

The design of an efficient computer-aided diagnosis (CADx) system for psoriasis severity assessment demands both accurate segmentation and classification of psoriasis lesions. Recently, few studies have been conducted to design automatic CADx systems for psoriasis severity assessment using traditional machine learning approaches. However, these approaches are highly featured dependent and require extensive and careful feature extraction. Among a large number of features extracted, assessing the features which contribute significantly to the classifier performing is a difficult and time-consuming task. Large features lead to poor generalization, due to high inter and intra-class variation of psoriasis skin lesions. This makes the task of implementing a reliable CADx system challenging. In such similar cases, Deep learning-based approaches have been proven better because of their ability to learn and make intelligent decisions automatically. In this study, a fully automated deep learning-based CADx system for psoriasis has been proposed. The system combines three modules in a single framework for achieving different objectives namely; recognition of psoriasis and non-psoriasis disease, automatic segmentation of psoriatic lesion, and its severity assessment. The modified U-Net and modified VGG-16 model have been implemented and trained for the segmentation and classification task respectively. The severity assessment module is capable of extracting discriminative features specifically related to the psoriatic lesion, which is automatically segmented by the segmentation module. The performance of the proposed CADx framework has been extensively evaluated on an extensive psoriasis dataset using k-fold cross-validation procedure. The appropriateness of the proposed system has been justified in terms of its performance at each of the three stages along with benchmarking against previously reported systems. Further, the system accuracy and reliability index has been evaluated for a dataset of varying size to validate the consistency of the proposed system.

The vitamin B6-regulated enzymes PYGL and G6PD fuel NADPH oxidases to promote skin inflammation

Psoriasis is a skin inflammatory disorder that affects 3% of the human population. Although several therapies based on the neutralization of proinflammatory cytokines have been used with relative success, additional treatments are required. The in silico analysis of gene expression data of psoriasis lesional skin and an analysis of vitamin B6 metabolites in the sera of psoriasis patients point to altered vitamin B6 metabolism at both local and systemic levels. Functional studies showed that vitamin B6 vitamers reduced skin neutrophil infiltration, oxidative stress and Nfkb activity in two zebrafish models of skin inflammation. Strikingly, inhibition of glycogen phosphorylase L (Pygl) and glucose-6-phosphate dehydrogenase (G6pd), two vitamin B6-regulated enzymes, alleviated oxidative-stress induced inflammation in zebrafish skin inflammation models. Despite the central role of G6pd in antioxidant defenses, the results of the study demonstrate that glycogen stores and G6pd fuel NADPH oxidase to promote skin inflammation, revealing novel targets for the treatment of skin inflammatory disorders.

Hyperproliferation is the main driver of metabolomic changes in psoriasis lesional skin

Systematic understanding of the metabolite signature of diseases may lead to a closer understanding of the disease pathogenesis and ultimately to the development of novel therapies and diagnostic tools. Here we compared for the first time the full metabolomic profiles of lesional and non-lesional skin biopsies obtained from plaque psoriasis patients and skin samples of healthy controls. Significant differences in the concentration levels of 29 metabolites were identified that provide several novel insights into the metabolic pathways of psoriatic lesions. The metabolomic profile of the lesional psoriatic skin is mainly characterized by hallmarks of increased cell proliferation. As no significant differences were identified between non-lesional skin and healthy controls we conclude that local inflammatory process that drives the increased cell proliferation is the main cause of the identified metabolomic shifts.

Retinol and vitamin A metabolites accumulate through RBP4 and STRA6 changes in a psoriasis murine model

BackgroundPsoriasis is a common chronic inflammatory skin disease that features the abnormal proliferation of keratinocytes. This proliferation could partly result from disturbances in vitamin A metabolism. Changes in psoriasis patients of the levels of retinol-binding protein 4 (RBP4), a carrier of retinol (vitamin A); transmembrane protein stimulated by retinoic acid 6 (STRA6); and other retinol metabolic molecules have not yet been fully established. Therefore, we investigated vitamin A-related proteins in mice with imiquimod (IMQ)-induced psoriasis.MethodsThirty mice were divided into four study groups: two groups underwent IMQ application for 3 or 6 days (groups A and B, respectively), and two groups underwent Vaseline application for 3 or 6 days (groups C and D, respectively). Blood and skin samples from both lesional and non-lesional areas of the mice were analyzed using enzyme-linked immunosorbent assays, hematoxylin and eosin staining, immunochemistry, real-time reverse transcription polymerase chain reaction, and RNA sequencing.ResultsIMQ-treated mice developed erythema, scales, and skin thickening. Compared with the control groups, IMQ-treated groups had the following changes: 1) interleukin (IL)-17A, IL-23, and tumor necrosis factor (TNF)-α levels were raised significantly in both serum and lesional skin (all p < 0.001); 2) retinol levels in lesional skin increased slightly (p = 0.364), but no change was evident in serum retinol levels; 3) STRA6 was upregulated in both lesional skin (p = 0.021) and serum (p = 0.034); 4) RBP4 levels were elevated in serum (p = 0.042), but exhibited only an increasing trend (p = 0.273) in lesional skin; and 5) proteins and enzymes that mediate retinoic acid formation and transformation were upregulated in lesional skin.ConclusionsAs the demand for vitamin A in psoriatic mice increased, retinol underwent relocation from the circulation to target tissues. RBP4, STRA6, and the transformation from retinol to retinoic acid were upregulated, which may be part of the mechanism of psoriasis skin lesion formation. We propose that a positive feedback mechanism was formed that maintained the severity of psoriasis.

Histologic comparison of tumor necrosis factor-α inhibitor–induced psoriasis and psoriasis vulgaris

Tumornecrosis factor-α inhibitor (TNFi)-induced psoriasis is a paradoxic reaction characterized by the development of a psoriasiform rash that mimics idiopathic psoriasis subtypes both clinically and histologically. Few studies have investigated the histologic features of TNFi-induced psoriasis skin lesions, and most of these are limited by inclusion of few specimens. We aimed to characterize histologic features of TNFi-induced psoriasis and identify histologic differences between TNFi-induced psoriasis and idiopathic psoriasis. We characterized 60 biopsy specimens obtained from 47 unique patients at a single tertiary care referral center between 2004 and 2016 who developed TNFi-induced psoriasis, and we compared histologic features to those of 85 biopsy specimens from a control group of 85 patients with idiopathic psoriasis. The most common histologic reaction pattern in TNFi-induced psoriasis biopsy specimens was psoriasiform (80.0%). Five histologic parameters were significantly different in TNFi-induced psoriasis biopsy specimens compared with idiopathic psoriasis biopsy specimens: at least 3 dermal eosinophils per histologic section, neutrophils in the stratum corneum, neutrophils in the epidermis, papillary plate thinning, and absence of parakeratosis. Inability to exclude lesion selection bias as a potential reason for some significant histologic differences. This study supports the idea that histologic differences exist between TNFi-induced psoriasis and idiopathic psoriasis may help distinguish between these conditions, especially for dermal eosinophil counts of 3 or greater.

Liraglutide improved inflammation via mediating IL-23/Th-17 pathway in obese diabetic mice with psoriasiform skin

Objectives The purpose of this study was to investigate the effect of liraglutide on obesity diabetic mice with psoriasiform skin inflammation. Methods Wild-type mice and db/db mice were randomly divided into five groups (n = 6): including the control group which received Vaseline, the imiquimod (IMQ)-induction group and the liraglutide-treatment group. The advanced treatment with liraglutide (0.3 mg/kg/d) for 4 weeks before IMQ induced psoriatic skin inflammation in the db/db + IMQ + Lira group. Basic parameters of diabetes, PASI, histopathology of skin, the expression of IL-17A, IL-23, IL-22, and TNF-α in the skin of back were measured. Results After IMQ induction, the psoriatic skin inflammation and pathological changes in the db/db + IMQ group were more serious than those in the WT + IMQ group. The glucose metabolism and insulin resistance of in the db/db + IMQ + Lira group were significantly improved, Psoriasis Area and Severity Index (PASI) was significantly reduced, and the protein and mRNA expressions of IL-23, IL-17, IL-22, and TNF-α in the back skin tissues were decreased. Conclusions Liraglutide can improve psoriasis skin lesions of obese diabetic mice, and the mechanism may be related to the inhibition of the expression of IL-23, IL-17, IL-22, and TNF-α through the IL-23/Th-17 pathway.

Ex vivo culture of lesional psoriasis skin for pharmacological testing

BackgroundPsoriasis is a chronic, inflammatory skin disorder resulting from a complex interplay between immune and skin cells via release of soluble mediators. While a lot is known about the molecular mechanisms behind psoriasis pathogenesis, there is still a need for preclinical research models that accuratelyreplicate the disease. ObjectiveThis study aimed to develop and characterize ex vivo culture of psoriasis skin as a model for pharmacological testing, where the immunological events of psoriasis can be followed. MethodsFull thickness punch biopsies of lesional psoriasis skin were cultured in submerged conditions up to 144 h followingin situ T cell stimulation with rhIL-23 and anti-CD3 and anti-CD28 antibodies. The T cell mediated skin inflammation was assessed by gene and protein l analysis for a panel of inflammatory mediators. Tissue integrity and morphology were evaluated by histological analysis. ResultsT cell stimulation resulted in functional and psoriasis specificin situ activation of T cells. The expression levels of most of the proinflammatory mediators related to both immune and skin cells were comparable to these in freshly isolated tissue at 48 and 96 h of culture. Tissue integrity and morphology were sustained up to 96 h. Treatment with a corticosteroid reduced the expression of several pro-inflammatory cytokines and chemokines, whereas anti-IL-17A antibody treatment reduced the expression of the IL-17A downstream markers IL-8 and DEFB4. ConclusionBy preserving keyimmunopathological mechanisms of psoriasis, ex vivo culture of psoriasis skin can be used for the investigation of inflammatory processes of psoriasis and for preclinical drug discovery research.

Mast Cells and Sensory Nerves Contribute to Neurogenic Inflammation and Pruritus in Chronic Skin Inflammation.

The intimate interaction between mast cells and sensory nerves can be illustrated by the wheal and surrounding flare in an urticarial reaction in human skin. This reaction is typically associated with an intense itch at the reaction site. Upon activation, cutaneous mast cells release powerful mediators, such as histamine, tryptase, cytokines, and growth factors that can directly stimulate corresponding receptors on itch-mediating sensory nerves. These include, e.g., H1- and H4-receptors, protease-activated receptor-2, IL-31 receptor, and the high-affinity receptor of nerve growth factor (TrkA). On the other hand, sensory nerves can release neuropeptides, including substance P and vasoactive intestinal peptide, that are able to stimulate mast cells to release mediators leading to potentiation of the reciprocal interaction, inflammation, and itch. Even though mast cells are well recognized for their role in allergic skin whealing and urticaria, increasing evidence supports the reciprocal function between mast cells and sensory nerves in neurogenic inflammation in chronic skin diseases, such as psoriasis and atopic dermatitis, which are often characterized by distressing itch, and exacerbated by psychological stress. Increased morphological contacts between mast cells and sensory nerves in the lesional skin in psoriasis and atopic dermatitis as well as experimental models in mice and rats support the essential role for mast cell-sensory nerve communication in consequent pruritus. Therefore, we summarize here the present literature pointing to a close association between mast cells and sensory nerves in pruritic skin diseases as well as review the essential supporting findings on pruritic models in mice and rats.

APOBEC3 regulates keratinocyte differentiation and expression of Notch3.

Apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like (APOBEC) family consists of deaminases. Some isozymes of APOBEC3 are induced upon human papillomavirus infection or development of psoriasis skin lesions. However, the involvement of APOBEC3 in keratinocyte differentiation has not been addressed. We herein sought to evaluate the roles of APOBECs in mouse primary keratinocyte differentiation. We found that expression levels of APOBEC1 and APOBEC3 were increased during calcium-induced keratinocyte differentiation. Unexpectedly, however, the expression levels of keratinocyte differentiation markers keratin 1/10, involucrin, loricrin and filaggrin were higher in keratinocytes treated with APOBEC3 siRNAs than in those treated with control RNAs. In addition, the treatment of keratinocytes with APOBEC3 siRNAs increased the gene expression levels of Notch3, a master regulator of keratinocyte differentiation. Moreover, calcium-induced increase in Notch3 expression and keratinocyte differentiation were impaired by transfection with an APOBEC3 expression plasmid. Furthermore, co-treatment with Notch3 siRNAs reduced the APOBEC3 siRNA-mediated upregulation of Notch3 expression and in part attenuated the increased expression levels of keratinocyte differentiation markers. These results suggest that APOBEC3 is induced upon keratinocyte differentiation and negatively regulates the keratinocyte differentiation in part by its inhibitory role for Notch3 expression.

154 MDR1-expressing T cells accumulate in the resolved skin of psoriatic plaque after treatment with topical corticosteroid but not with anti-IL-17A mAb

Topical corticosteroid is a widely used for treatment of psoriasis. However, its long-term use may bring about resistance to the treatment. We have previously shown that multiple drug resistance 1 (MDR1)-expressing T cells infiltrate in the skin lesions of psoriasis, especially at the skin treated with a corticosteroid. Corticosteroids are a substrate of MDR1, and possible association of MDR1+ T cells and corticosteroid resistance has been documented in some diseases. Since MDR1+ T cells in psoriatic skin include a large number of IL-17A and IL-22-producing cells, they can be associated with corticosteroid resistance. In this study, we sought to clarify whether the blockade of IL-17A by Secukinumab affects MDR1 expression. We analyzed stocked T cells expanded by IL-2 and anti-CD3/CD28 mAb-coated microbeads from biopsy specimens taken from the skin of 7 patients treated with topical corticosteroid and from the skin of 6 patients treated with Secukinumab. The function of MDR1 was investigated by Rh123 efflux assay. Rh123low cells expressed ABCB1 gene, while Rh123hi cells did not. In addition, verapamil, a specific inhibitor of MDR1 depressed the efflux of Rh123 at 94.0±2.3 percent, and thus, we considered Rh123low cells as MDR1+ cells. In vitro treatment of a corticosteroid significantly increased the frequency of MDR1+ cells (P=0.02). The frequency of MDR1+ T cells was significantly higher in the corticosteroid-treated skin than in Secukinumab-treated patients’ skin (P=0.01). Notably, this difference was more apparent in CD4+ T cells than in CD8+ T cells. Our results suggest that, unlike corticosteroid-treated skin, MDR1+ T cells do not accumulate in the skin of Secukinumab-treated patients. While anti-IL-17A mAb more strongly improves psoriasis than do topical corticosteroids, it renders remaining skin T cells susceptible to corticosteroid treatment.

360 miR-378a is overexpressed in psoriasis keratinocytes and potentiates IL-17A-mediated inflammatory responses

Psoriasis is an immune-mediated inflammatory skin disease with a strong genetic background, in which an interplay between infiltrating immune cells and keratinocytes contributes to chronic skin inflammation. The cytokine IL-17, produced by Th17 cells and other cell types, is central in the pathogenesis, and its main target cells are keratinocytes in which it induces cytokines, chemokines and antimicrobial peptides, which further amplify inflammation. Recently, we performed next-generation sequencing for small RNAs in keratinocytes separated by magnetic sorting of CD45neg cells from the epidermis from lesional and non-lesional skin from psoriasis patients. One of the miRNAs differentially expressed in psoriasis keratinocytes was miR-378a. Here, we investigated the function of miR-378a in keratinocytes in psoriasis. miR-378a was significantly up-regulated in keratinocytes of psoriasis skin lesions, as evidenced by RNAseq as well as qPCR on sorted keratinocytes obtained from a larger patient cohort. To investigate the regulation of miR-378a, cultured primary human keratinocytes were treated with a panel of cytokines. qPCR expression analysis of miR-378a showed that IL-17A significantly induced miR-378a, while other cytokines studied did not affect its expression. The NF-kB pathway inhibitor BAY 11-7082 prevented the induction of miR-378a by IL17A, indicating that miR-378a is regulated through the NF-kB pathway. Overexpression of miR-378a in primary keratinocytes potentiated IL-17A-mediated induction of inflammatory mediators in keratinocytes, such as the cytokines CCL20 and IL-8, and the antimicrobial peptide hBD2. Our findings suggest that upregulation of miR-378a in keratinocytes of psoriasis lesions enhances their inflammatory response to IL-17A, thereby amplifying IL-17A-mediated inflammation. Inhibition of miR-378a may have therapeutic potential in psoriasis.

E-cadherin expression in lesional and nonlesional psoriasis skin

E-cadherin expression in lesional and nonlesional psoriasis skin

Quantification of randomness (Entropy) as a clinical tool to assess the severity of skin disease

In today’s medical practice, the approach towards quantitative analysis of the skin is considered to be challenging and subjective. The current accepted measures and indexes do not exhibit a universal measurement, carry subjective opinions, and vary from one assessor to another. We propose a novel promising technique that provides a universal measure of various skin conditions which accesses the severity of skin disease in a quantitative manner. In this paper, we describe a clinical tool which provides a quantitative analysis of the skin using a mathematical algorithm of calculating Maximum entropy. The current work had been based on assessing skin lesions of psoriasis as a prototypic disease and adjacent healthy skin of patients in order to prove the concept of using computing entropy results to assess the skin condition. From the collected data of 11 pairs of the diseased and clinically healthy skin, the healthy skin displayed lower Entropy values with mean μ = 2.56 ± 0.10 while skin affected by psoriasis displayed higher Entropy values with mean μ = 3.30 ± 0.19.

Bacteriophage of the Skin Microbiome in Patients with Psoriasis and Healthy Family Controls

The bacteriophage (phage) component of the skin microbiome in patients with psoriasis has not been systematically explored. The purpose of this study is to investigate phage and bacterial components of the skin microbiome in patients with psoriasis and in healthy family controls. Lesional skin swabs of four different locations (elbow, forearm, knee, and scalp) were taken from patients with psoriasis. Healthy skin swabs of matched locations were taken from contralateral non-lesional skin and healthy family controls. Skin microbiomes were investigated using next-generation shotgun metagenomics sequencing. 81 skin microbiome samples (27 lesional skin samples and 54 healthy skin samples from contralateral non-lesional skin and family controls) obtained from 16 subjects with psoriasis and 16 matched family controls were sequenced and analyzed. Among phage species with abundant host bacteria, two significantly differential abundant phage species, Acinetobacter phage Presley and Pseudomonas phage O4 (adjusted P < 0.05), between psoriasis lesional skin and healthy skin were identified. Samples with high levels of these phage species had their host bacteria abundance suppressed (P= 0.03 and P < 0.001). Differential phage composition between lesional skin in patients with psoriasis and healthy skin from contralateral non-lesional sites and family controls, as well as the suppression of bacteria host of the respective phage, suggest possible avenues for probiotic phage therapeutics.

Differential occurrence of lysine 2-hydroxyisobutyrylation in psoriasis skin lesions

Lysine 2-hydroxyisobutyrylation is a newly discovered posttranslational modification. Although this modification is an important type of protein acylation, its role in psoriasis remains unstudied. We compared lesional and nonlesional psoriasis skin samples from 45 psoriasis patients. The result showed that this highly conserved modification was found in large quantities in both normal and diseased dermal tissues. However, there were a number of clear and significant differences between normal and diseased skin tissue. By comparing, lysine 2-hydroxyisobutyrylation was upregulated at 94 sites in 72 proteins and downregulated at 51 sites in 44 proteins in lesional skin. In particular, the sites with the most significant downregulation of lysine 2-hydroxyisobutyrylation were found in S100A9 (ratio = 0.140, p-value = .000371), while the most upregulated site was found in tenascin (ratio = 3.082, p-value = .0307). Loci associated with psoriasis, including FUBP1, SERPINB2 and S100A9, also exhibited significant regulation. Analyses of proteome data revealed that SERPINB2 and S100A9 were differentially expressed proteins. And bioinformatics analysis suggest that the P13K-Akt signaling pathway was more enriched with lysine 2-hydroxyisobutyrylation in lesional psoriasis skin. Our study revealed that lysine 2-hydroxyisobutyrylation is broadly present in psoriasis skin, suggesting that this modification plays a role in psoriasis pathogenesis. SignificanceA newly discovered protein posttranslational modification, lysine 2-hydroxyisobutyrylation, has been found to occur in a wide variety of organisms and to participate in some important metabolic processes. In this study, lysine 2-hydroxyisobutyrylation in lesional psoriasis skin and nonlesional psoriasis skin was quantified and compared for the first time. We found a number of differentially modified proteins and sites in our comparisons. Interestingly, some of the identified proteins and pathways with significantly different modifications, such as S100A9 and the PI3K-Akt signaling pathway, have been previously reported to be associated with psoriasis. We hope that this research will provide new insights into 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.