Identification of key apoptosis-related genes and immune infiltration in the pathogenesis of psoriasis.
Hereditas
BACKGROUND:Psoriasis is a condition in which skin cells build up and form itchy scales and dry patches. It is also considered a common lifelong disease with an unclear pathogenesis. Furthermore, an effective cure for psoriasis is still unavailable. Reductive apoptosis of keratinocytes and immune infiltration are common in psoriasis. This study aimed to explore underlying functions of key apoptosis-related genes and the characteristics of immune infiltration in psoriasis. We used GSE13355 and GSE30999 to screen differentially expressed apoptosis related genes (DEARGs) in our study. Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway, and gene set enrichment analysis (GSEA) were performed using clusterProfiler package. Protein-protein interaction (PPI) network was constructed to acquire key DEARGs. Transcription factor (TF)-target and miRNA-mRNA network analyses, drug sensitivity prediction, and immune infiltration were applied. Key DEARGs were validated using real-time quantitative PCR (RT-qPCR). RESULTS:We identified 482 and 32 DEARGs from GSE13355 and GSE30999, respectively. GO analysis showed that DEARGs were commonly enriched in cell chemotaxis, receptor ligand activity, and signaling receptor activator activity. KEGG pathway analysis indicated that viral protein interaction with cytokine and cytokine receptor was maximally enriched pathway. The GSEA analysis of GSE13355 and GSE30999 demonstrated a high consistency degree of enriched pathways. Thirteen key DEARGs with upregulation were obtained in the PPI network. Eleven key DEARGs were confirmed using RT-qPCR. Additionally, 5 TFs and 553 miRNAs were acquired, and three novel drugs were predicted. Moreover, Dendritic.cells.activated exhibited high levels of immune infiltration while Mast.cells.resting showed low levels of immune infiltration in psoriasis groups. CONCLUSION:Results of this study may reveal some insights into the underlying molecular mechanism of psoriasis and provide novel targeted drugs.
10.1186/s41065-022-00233-0
The Effectiveness and Safety of Probiotic Supplements for Psoriasis: A Systematic Review and Meta-Analysis of Randomized Controlled Trials and Preclinical Trials.
Journal of immunology research
BACKGROUND:Patients with psoriasis need long-term medication to control their condition. Recent studies suggest that changing the intestinal flora may be a potential treatment. METHODS:The databases were utilized to search the randomized controlled trials (RCTs) and preclinical trials about probiotic supplement in the treatment of psoriasis. The retrieval time is from the establishment of these databases to December 2020. RevMan5.3 was used for the risk assessment of bias and meta-analysis. This systematic review was registered in PROSPERO (CRD42021232756). RESULTS:A total of 3 RCTs involving 164 participants were included. Two RCTs showed that probiotics can improve PASI and thereby improve the condition. For inflammation-related indicators, only one RCT showed that probiotics can improve the levels of CRP and TNF- but have no obvious improvement effect on IL6. One RCT demonstrated the total effective rate of probiotics in the treatment of psoriasis. For adverse events, one RCT showed that the incidence of adverse events of probiotic treatment was low. Preclinical studies showed that continuous intervention with oral probiotics can significantly improve the progression of psoriasis and reduce the expression of inflammatory factors. The meta-analysis showed that the PASI between two groups was of no statistical significance (SMD 1.83 [-0.41, 4.07], = 0.11). Meanwhile, probiotics may improve skin thickness (SMD -5.87 [-11.34, -0.41], = 0.04) in animal model. CONCLUSION:Prebiotics may have a positive effect on alleviating the clinical symptoms of psoriasis, but a large sample of RCTs is still needed to support its therapeutic effect in psoriasis.
10.1155/2021/7552546
The Immunogenetics of Psoriasis.
Advances in experimental medicine and biology
Psoriasis vulgaris is a chronic immune-mediated dermatological condition, resulting from an interaction between environmental triggers and genetic susceptibilities. Alteration in the production of the inflammatory mediators plays a pivotal part in the pathogenesis of the disease. Genes encoding the mediators of these inflammatory pathways can dictate susceptibility to psoriasis. These genes have a wide range of functions that involve innate immunity (IFIH1, TRAF3IP2, CARD14, c-REL, DDX58), antigen presentation (HLA-Cw6), T-cells development, maturation, and polarization (RUNX1, RUNX3, STAT3), cytokine signaling (IL12Bp40, IL23Ap19, IL23R, JAK2), and immune regulators (TNIP1, TNFAIP3, IL36RN, SOCS1, ZC3H12C, NFKBIA). The risk alleles of these genes can contribute to the overall state of susceptibility to psoriasis by lowering the threshold of the innate immune response that can eventually provoke the pathogenic adaptive immune responses capable of inducing psoriasis. The investigations on genetic associations of psoriasis may allow the discovery of new diseases modifying targets and possibly open a path for the advancement of personalized medicine. They also allow us to discover new aspects of human skin biology.
10.1007/978-3-030-92616-8_4
Comparison of gut microbiota compositions and corresponding genetic and metabolic features between guttate and plaque psoriasis by metagenomic sequencing.
Microbial pathogenesis
BACKGROUND:Guttate psoriasis (GP) and psoriasis plaques (PP) are common subtypes of psoriasis. Previous studies have fully researched the association between psoriasis and gut microbiota. However, the differences in gut microbiota between GPs and PPs are still unknown. METHODS:Fecal samples were collected from 30 psoriatic patients (15 GP and 15 PP) and 15 healthy subjects. Metagenomic sequencing was then used to compare gut microbiota compositions and corresponding genetic and metabolic features between GP and PP. RESULTS:We found that the genus Megamonas was increased in PP and reduced in GP. The genus Eubacterium was increased in GP and decreased in PP. Ten KEGG pathway were significantly enriched in GP: bacterial secretion system, ribosome, sphingolipid signaling pathway, steroid hormone biosynthesis, complement and coagulation cascades, proteoglycans in cancer, FOXO signaling pathway, cGMP-PKG signaling pathway, insulin resistance, and Epstein-Barr virus infection. Ten metabolites were significantly differentially abundant between GP and PP. Among them, thiamine, biotin, butylamine, phenylethylamine, folic acid, 1,2-propanediol, and 4-aminobutyrate were enriched in PP and l-glutamate, l-glutamine, and propanoate were enriched in GP. CONCLUSIONS:These results provide a theoretical basis for the microbiome-guided stratification of patients with psoriasis.
10.1016/j.micpath.2022.105560
Gut dysbiosis in cutaneous T-cell lymphoma is characterized by shifts in relative abundances of specific bacterial taxa and decreased diversity in more advanced disease.
Journal of the European Academy of Dermatology and Venereology : JEADV
BACKGROUND:Cutaneous T-cell lymphoma (CTCL) patients often suffer from recurrent skin infections and profound immune dysregulation in advanced disease. The gut microbiome has been recognized to influence cancers and cutaneous conditions; however, it has not yet been studied in CTCL. OBJECTIVES:To investigate the gut microbiome in patients with CTCL and in healthy controls. METHODS:A case-control study was conducted between January 2019 and November 2020 at Northwestern's busy multidisciplinary CTCL clinic (Chicago, Illinois, USA) utilizing 16S ribosomal RNA gene amplicon sequencing and bioinformatics analyses to characterize the microbiota present in fecal samples of CTCL patients (n = 38) and age-matched healthy controls (n = 13) from the same geographical region. RESULTS:Gut microbial α-diversity trended lower in patients with CTCL and was significantly lower in patients with advanced CTCL relative to controls (P = 0.015). No differences in β-diversity were identified. Specific taxa were significantly reduced in patient samples; significance was determined using adjusted P-values (q-values) that accounted for a false discovery rate threshold of 0.05. Significantly reduced taxa in patient samples included the phylum Actinobacteria (q = 0.0002), classes Coriobacteriia (q = 0.002) and Actinobacteria (q = 0.03), order Coriobacteriales (q = 0.003), and genus Anaerotruncus (q = 0.01). The families Eggerthellaceae (q = 0.0007) and Lactobacillaceae (q = 0.02) were significantly reduced in patients with high skin disease burden. CONCLUSIONS:Gut dysbiosis can be seen in patients with CTCL compared to healthy controls and is pronounced in more advanced CTCL. The taxonomic shifts associated with CTCL are similar to those previously reported in atopic dermatitis and opposite those of psoriasis, suggesting microbial parallels to the immune profile and skin barrier differences between these conditions. These findings may suggest new microbial disease biomarkers and reveal a new angle for intervention.
10.1111/jdv.18125
Small plaque psoriasis re-visited: A type of psoriasis mediated by a type-I interferon pathway.
Experimental dermatology
TNFα-inhibitor-induced psoriasis is mediated by the type-I interferon pathway, of which IFNα, LL37 and IL-36γ are major players. A subset of patients treated with TNFα inhibitors develop small plaque psoriatic lesions. Small plaque psoriasis is similarly observed in patients on immune checkpoint inhibitors (ICI), and with concurrent systemic lupus erythematosus (SLE) or positive antinuclear antibody (ANA). Small plaque psoriasis is also the predominant phenotype in Asian populations. The association between small plaque psoriasis morphology in various clinical scenarios and the type-I interferon pathway has not been previously studied. A cross-sectional study was conducted of patients who developed small plaque psoriasis and had a biopsy for diagnostic clarification between 2009 and 2017. We obtained skin specimens from 14 adults with small plaque psoriasis: four patients taking anti-TNFα treatment, four patients with antecedent SLE, three patients with concurrent ANA positivity and three patients taking ICI. Controls included three patients with chronic plaque psoriasis. Histology confirmed psoriasiform epidermal hyperplasia with focal lichenoid and spongiotic features. Immunohistochemical analysis revealed higher expression of IFNα-induced MXA, LL37 and IL-36γ in all clinical scenarios of small plaque psoriasis compared to chronic plaque psoriasis. There was decreased CD8 T-cell migration to the epidermis and variability in the number of LAMP3+ cytoplasmic dendritic cells in the dermis of small plaque psoriasis. The findings suggest that small plaque psoriasis is a unique type of psoriasis with a distinct morphology and immune-phenotype, primarily mediated by the type-I interferon pathway. Associating morphology and disease pathogenesis may help identify therapeutic targets for better disease control.
10.1111/exd.14513
Ustekinumab reduces serum protein levels associated with cardiovascular risk in psoriasis vulgaris.
Experimental dermatology
Psoriasis increases the risk of cardiovascular disease (CVD). Biomarkers for cardiovascular (CV) risk stratification in psoriasis are lacking, and the effects of psoriasis biologics on CV risk reduction remain unclear. The goal of this study was to identify biomarkers of CV risk in psoriasis blood that are reduced by ustekinumab. We quantified 276 inflammatory and CV-related serum proteins with Olink's multiplex assay in 10 psoriasis patients (vs. 18 healthy controls) and after 12 weeks of ustekinumab treatment. For each protein down-regulated after treatment, the literature was reviewed for studies assessing the protein's association with CVD. Data were collected from each study to calculate CV risk thresholds for each protein, which were compared with protein levels in psoriasis patients before and after treatment. Our results showed that 43 out of 276 proteins were down-regulated after treatment, 25 of which were initially up-regulated at baseline (vs. controls, all p-values ≤0.1). 8 down-regulated proteins were initially elevated above thresholds associated with enhanced CV risk in the literature (myeloperoxidase, C-X-C motif chemokine 10, E-selectin, interleukin-6, cystatin B, von Willebrand factor, tumor necrosis factor receptor 1 and N-terminal prohormone brain natriuretic peptide). Treatment lowered these proteins to below their risk thresholds, except for IL-6, which was lowered but remained at its risk threshold despite successful psoriasis skin treatment. In summary, 12 weeks of ustekinumab treatment reduced serum proteins present at levels associated with CV risk in psoriasis patients. Further studies can evaluate these proteins as potential ustekinumab-modulated biomarkers of CV risk in psoriasis and the impact of ustekinumab on CV risk reduction.
10.1111/exd.14582
Cellular Molecular of Osteopontin in the Pathogenesis of Psoriasis.
FASEB journal : official publication of the Federation of American Societies for Experimental Biology
Psoriasis (PS) is a chronic inflammatory skin disease of complex pathogenesis with genetic predisposition, environmental factors and immunological disturbances. Osteopontin (OPN) is known to enhance Th1 responses, inhibit Th2 ones, and take part in the modulation of Th17 cell lineage. Due to its impact on Th1/Th17 immune responses, several reports have suggested that OPN may be of pathogenic importance in psoriasis. However, the involvement of this OPN in the onset of psoriasis have not been fully elucidated. We investigate the cellular localization of OPN protein expression and histopathological features of psoriasis. The study was conducted on 40 patients affected with plaque psoriasis, 10 healthy volunteers and ER+ breast cancer as a positive control. Severity of PS was assessed using the qualitative assessment and severity index score. Our results showed statistically significant differences in the expression of OPN, between lesional and non lesional skin as well as between non lesional skin and control group (P ≤ 0.05). In addition, there was a significant difference in the expression of OPN, between control and lesional group. We concluded that, OPN expressions and severity of psoriasis showed a strong significant negative correlation and also a moderate significant negative correlation. With this notion we postulate OPN expressions will stimulate the inflammatory response, by generating anti-OPN antibodies and eventually determining OPN expression will become a useful therapeutic tool in assessing and establishing early detection of PS.
10.1096/fasebj.2022.36.S1.L7422
Free Fatty Acid Receptor 4 (FFA4) Activation Ameliorates Imiquimod-Induced Psoriasis in Mice.
International journal of molecular sciences
Dietary supplementation with n-3 polyunsaturated fatty acids (n-3 PUFA) has been used as an adjunct therapy for psoriasis due to its anti-inflammatory properties. Free fatty acid receptor 4 (FFA4 or GPR120) is a receptor-sensing n-3 PUFA. In the present study, we examined whether FFA4 acted as a therapeutic target for n-3 PUFA in psoriasis therapy. Experimentally, psoriasis-like skin lesions were induced by treatment with imiquimod for 6 consecutive days. A selective FFA4 agonist, Compound A (30 mg/kg), was used in FFA4 WT and FFA4 KO mice. Imiquimod-induced psoriasis-like skin lesions, which present as erythematous papules and plaques with silver scaling, as well as markedly elevated IL-17/IL-23 cytokine levels in skin tissues, were significantly suppressed by Compound A in FFA4 WT mice, but not in FFA4 KO mice. Enlarged lymph nodes and spleens, as well as imiquimod-induced, elevated IL-17/IL-23 cytokine levels, were also strongly suppressed by Compound A in FFA4 WT mice, but not in FFA4 KO mice. Imiquimod-induced increases in the CD4IL-17A T cell population in lymph nodes and spleens were suppressed by Compound A treatment in FFA4 WT mice; however, this was not seen in FFA4 KO mice. Furthermore, compound A suppressed the differentiation of CD4 naïve T cells from splenocytes into T17 cells in an FFA4-dependent manner. In conclusion, we demonstrated that the activation of FFA4 ameliorates imiquimod-induced psoriasis, and the suppression of the differentiation of T17 cells may partly contribute to its efficacy. Therefore, we suggest that FFA4 could be a therapeutic target for psoriasis therapy.
10.3390/ijms23094482
Exploration of the Potential Mechanism of the Common Differentially Expressed Genes in Psoriasis and Atopic Dermatitis.
BioMed research international
Backgrounds:Psoriasis and atopic dermatitis are two common chronic inflammatory skin diseases that enormously deteriorate the psycho-physical and socio-economic condition of the patients. Although differential immune responses have been found to operate in the pathomechanisms of atopic dermatitis and psoriasis, the epidermal keratinocytes are the major targets in both diseases, and sometimes, they show similar clinical presentations. The skin barrier, itching, and inflammation are current and future treatment targets for both of them, but the relevant shared mechanisms of the two diseases are far from understood. Methods:The differential analyses of GSE14905 (psoriasis) and GSE32924 (atopic dermatitis) deposited in GEO database were conducted and obtained their differential expressed genes. Moreover, PPI, functional modules, GO, and KEGG enrichment analyses were used for the further analysis. The mouse models of psoriasis and atopic dermatitis were established, and then, RT-qPCR and Western blotting assay were performed to check the abundant changes of hub genes. Results:There are 732 differentially expressed genes in psoriasis versus nonlesional skin samples. Besides, 611 differentially expressed genes were identified in atopic dermatitis versus nonlesional skin data sets. Based on these differentially expressed genes, we predicted their joint and individual protein-protein interaction networks and functional modules in both psoriasis and atopic dermatitis. Through the PPI network of genes, we calculated the hub nodes and do the GO and KEGG enrichment analysis of overlapped genes of psoriasis and atopic dermatitis, which suggested there were some terms like "positive regulation of interleukin-12 production," "centromeric region," and "TNF signaling pathway." Conclusion:We constructed the predicted PPI networks and functional modules related to psoriasis and atopic dermatitis and distinguished the key candidate target genes , , and in the diagnosis and therapy of similar pathogenesis.
10.1155/2022/1177299