Skin Patterning in Psoriasis by Spatial Interactions between Pathogenic Cytokines.
Ontology highlight
ABSTRACT:
SUBMITTER: Ringham L
PROVIDER: S-EPMC6835055 | biostudies-literature | 2019 Oct
REPOSITORIES: biostudies-literature
Publications
Skin Patterning in Psoriasis by Spatial Interactions between Pathogenic Cytokines.
Ringham Lee L Prusinkiewicz Przemyslaw P Gniadecki Robert R
iScience 20191007
Disorders of human skin manifest themselves with patterns of lesions ranging from simple scattered spots to complex rings and spirals. These patterns are an essential characteristic of skin disease, yet the mechanisms through which they arise remain unknown. Here we show that all known patterns of psoriasis, a common inflammatory skin disease, can be explained in terms of reaction-diffusion. We constructed a computational model based on the known interactions between the main pathogenic cytokine ...[more]
Similar Datasets
Project description:Psoriasis is a common inflammatory skin disease with an incompletely understood etiology. The disease is characterized by red, scaly and well-demarcated skin lesions formed by the hyperproliferation of epidermal keratinocytes. This hyperproliferation is driven by cytokines secreted by activated resident immune cells, an infiltrate of T cells, dendritic cells and cells of the innate immune system, as well as the keratinocytes themselves. Psoriasis has a strong hereditary character and has a complex genetic background. Genome-wide association studies have identified polymorphisms within or near a number of genes encoding cytokines, cytokine receptors or elements of their signal transduction pathways, further implicating these cytokines in the psoriasis pathomechanism. A considerable number of inflammatory cytokines have been shown to be elevated in lesional psoriasis skin, and the serum concentrations of a subset of these also correlate with psoriasis disease severity. The combined effects of the cytokines found in psoriasis lesions likely explain most of the clinical features of psoriasis, such as the hyperproliferation of keratinocytes, increased neovascularization and skin inflammation. Thus, understanding which cytokines play a pivotal role in the disease process can suggest potential therapeutic targets. A number of cytokines have been therapeutically targeted with success, revolutionizing treatment of this disease. Here we review a number of key cytokines implicated in the pathogenesis of psoriasis.
| S-EPMC4437803 | biostudies-literature
Project description:Psoriasis is an immune-mediated inflammatory skin disease that affects millions worldwide. Studying immune cells involved in psoriasis pathogenesis is essential to identify effective and safe therapeutics for the disease. Using human psoriasis skin, activated macrophages were observed in both lesional and non-lesional skin, but were elevated in lesional skin. Activation of the IL-23/IL-17 pathway is integral to the development of psoriasis. To further characterize the monocyte/macrophage (Mon/Mac) population when the IL-23 pathway is activated, a murine model of intradermal injection of IL-23 was used. Flow cytometry revealed that Mon/Mac cells were the dominant immune population, particularly late in the model, highlighted by strong presence of Ly6ChiMHC IIhi cells. The Mon/Mac cells were also shown to have high expression for TNFα but not IL-17A. Prophylactic dosing of a CSF-1R inhibitor to deplete Mon/Mac cells significantly reduced several inflammatory mediators from the skin tissue suggesting a pathogenic role for Mon/Mac. Treatment dosing of the inhibitor produced a less robust effect. Mon/Mac cells were also differentiated by levels of Ki67 and TNFα expression. These data point to an important contribution of Mon/Mac cells in IL-23 related skin inflammation and suggest that these cells are a significant player in the underlying pathophysiology of psoriasis.
| S-EPMC6441056 | biostudies-literature
Project description:Herein we demonstrate the efficacy of an unbiased proteomics screening approach for studying protein expression changes in the KC-Tie2 psoriasis mouse model, identifying multiple protein expression changes in the mouse and validating these changes in human psoriasis. KC-Tie2 mouse skin samples (n=3) were compared with littermate controls (n=3) using gel-based fractionation followed by label-free protein expression analysis. 5482 peptides mapping to 1281 proteins were identified and quantitated: 105 proteins exhibited fold-changes ≥2.0 including: stefin A1 (average fold change of 342.4 and an average P = 0.0082; cystatin A, human orthologue); slc25a5 (average fold change of 46.2 and an average P = 0.0318); serpinb3b (average fold change of 35.6 and an average P = 0.0345; serpinB1, human orthologue); and kallikrein related peptidase 6 (average fold change of 4.7 and an average P = 0.2474; KLK6). We independently confirmed mouse gene expression-based increases of selected genes including serpinb3b (17.4-fold, P < 0.0001), KLK6 (9.0-fold, P = 0.002), stefin A1 (7.3-fold; P < 0.001) and slc25A5 (1.5-fold; P = 0.05) using qRT-PCR on a second cohort of animals (n=8). Parallel LC/MS/MS analyses on these same samples verified protein-level increases of 1.3-fold (slc25a5; P < 0.05), 29,000-fold (stefinA1; P < 0.01), 322-fold (KLK6; P < 0.0001) between KC-Tie2 and control mice. To underscore the utility and translatability of our combined approach, we analyzed gene and protein expression levels in psoriasis patient skin and primary keratinocytes vs. healthy controls. Increases in gene expression for slc25a5 (1.8-fold), cystatin A (3.0-fold), KLK6 (5.8-fold) and serpinB1 (76-fold; all P < 0.05) were observed between healthy controls and involved lesional psoriasis skin and primary psoriasis keratinocytes. Moreover slc25a5, cystatin A, KLK6 and serpinB1 protein were all increased in lesional psoriasis skin compared to normal skin. These results highlight the usefulness of preclinical disease models using readily-available mouse skin and demonstrate the utility of proteomic approaches for identifying novel peptides/proteins that are differentially regulated in psoriasis that could serve as sources of auto-antigens or provide novel therapeutic targets for the development of new anti-psoriatic treatments.
2014-10-30 | PXD001387 | Pride
Project description:Tree spatial patterns in dry coniferous forests of the western United States, and analogous ecosystems globally, were historically aggregated, comprising a mixture of single trees and groups of trees. Modern forests, in contrast, are generally more homogeneous and overstocked than their historical counterparts. As these modern forests lack regular fire, pattern formation and maintenance is generally attributed to fire. Accordingly, fires in modern forests may not yield historically analogous patterns. However, direct observations on how selective tree mortality among pre-existing forest structure shapes tree spatial patterns is limited. In this study, we (a) simulated fires in historical and contemporary counterpart plots in a Sierra Nevadan mixed-conifer forest, (b) estimated tree mortality, and (c) examined tree spatial patterns of live trees before and after fire, and of fire-killed trees. Tree mortality in the historical period was clustered and density-dependent, because trees were aggregated and segregated by tree size before fire. Thus, fires maintained an aggregated distribution of tree groups. Tree mortality in the contemporary period was widespread, except for dispersed large trees, because most trees were a part of large, interconnected tree groups. Thus, postfire tree patterns were more uniform and devoid of moderately sized tree groups. Postfire tree patterns in the historical period, unlike the contemporary period, were within the historical range of variability identified for the western United States. This divergence suggests that decades of forest dynamics without significant disturbances have altered the historical means of pyric pattern formation. Our results suggest that ecological silvicultural treatments, such as forest restoration thinnings, which emulate qualities of historical forests may facilitate the reintroduction of fire as a means to reinforce forest structural heterogeneity.
| S-EPMC7820164 | biostudies-literature
Project description:Viruses must efficiently and specifically package their genomes while excluding cellular nucleic acids and viral sub-genomic fragments. Some viruses use specific packaging signals, which are conserved sequence/structure motifs present only in the full-length genome. Recent work has shown that viral proteins important for packaging can undergo liquid-liquid phase separation (LLPS), where one or two viral nucleic acid binding proteins condense with the genome. The compositional simplicity of viral components lends itself well to theoretical modeling compared to more complex cellular organelles. Viral LLPS can be limited to one or two viral proteins and a single genome that is enriched in LLPS-promoting features. In our previous study, we observed that LLPS-promoting sequences of SARS-CoV-2 are located at the 5' and 3' ends of the genome, whereas the middle of the genome is predicted to consist mostly of solubilizing elements. Is this arrangement sufficient to drive single genome packaging, genome compaction, and genome cyclization? We addressed these questions using a coarse-grained polymer model, LASSI, to study the LLPS of nucleocapsid protein with RNA sequences that either promote LLPS or solubilization. With respect to genome cyclization, we find the most optimal arrangement restricts LLPS-promoting elements to the 5' and 3' ends of the genome, consistent with the native spatial patterning. Genome compaction is enhanced by clustered LLPS-promoting binding sites, while single genome packaging is most efficient when binding sites are distributed throughout the genome. These results suggest that many and variably positioned LLPS-promoting signals can support packaging in the absence of a singular packaging signal which argues against necessity of such a feature. We hypothesize that this model should be generalizable to multiple viruses as well as cellular organelles like paraspeckles, which enrich specific, long RNA sequences in a defined arrangement.
| S-EPMC7805453 | biostudies-literature
Project description:Viruses must efficiently and specifically package their genomes while excluding cellular nucleic acids and viral subgenomic fragments. Some viruses use specific packaging signals, which are conserved sequence or structure motifs present only in the full-length genome. Recent work has shown that viral proteins important for packaging can undergo liquid-liquid phase separation (LLPS), in which one or two viral nucleic acid binding proteins condense with the genome. The compositional simplicity of viral components lends itself well to theoretical modeling compared with more complex cellular organelles. Viral LLPS can be limited to one or two viral proteins and a single genome that is enriched in LLPS-promoting features. In our previous study, we observed that LLPS-promoting sequences of severe acute respiratory syndrome coronavirus 2 are located at the 5' and 3' ends of the genome, whereas the middle of the genome is predicted to consist mostly of solubilizing elements. Is this arrangement sufficient to drive single genome packaging, genome compaction, and genome cyclization? We addressed these questions using a coarse-grained polymer model, LASSI, to study the LLPS of nucleocapsid protein with RNA sequences that either promote LLPS or solubilization. With respect to genome cyclization, we find the most optimal arrangement restricts LLPS-promoting elements to the 5' and 3' ends of the genome, consistent with the native spatial patterning. Genome compaction is enhanced by clustered LLPS-promoting binding sites, whereas single genome packaging is most efficient when binding sites are distributed throughout the genome. These results suggest that many and variably positioned LLPS-promoting signals can support packaging in the absence of a singular packaging signal which argues against necessity of such a feature. We hypothesize that this model should be generalizable to multiple viruses as well as cellular organelles such as paraspeckles, which enrich specific long RNA sequences in a defined arrangement.
| S-EPMC8241574 | biostudies-literature
Project description:Adiposity is a known risk factor for psoriasis. Genome-wide association studies (GWAS) have identified a number of genes associated with risk of psoriasis while the evidence on gene-environment interactions in psoriasis is very sparse.To investigate the effect modification by adiposity measures on the association between single-nucleotide polymorphisms (SNPs) from published GWAS and risk of psoriasis.Our psoriasis GWAS dataset comprised 9194 participants, including 337 individuals with psoriasis and 8857 controls from six GWAS, nested within the Nurses' Health Study (NHS), NHS II, and Health Professionals' Follow-up Study. Clinician-diagnosed psoriasis was ascertained with high validity. For stratified analyses, body mass index (BMI) was dichotomized at 25, and waist circumference was dichotomized at 30 (women) and 36 inches (men), while waist-hip ratio (WHR) was dichotomized at 0·8 (women) and 1·0 (men).Forty-one out of 44 previously reported psoriasis-related SNPs were included in our GWAS datasets. After excluding those with high linkage disequilibrium, 33 remained in the analysis. There were significant interactions between BMI and two SNPs in the IL12B (rs3212227) and IL23R (rs7530511) genes. Further analysis of these two SNPs indicated interactions between rs3212227 and waist circumference or WHR [P for interaction (P )?<?0·05], but not for rs7530511. These observations were confirmed among participants without type 2 diabetes or coronary heart disease. The interactions remained after simultaneously adjusting for BMI as a continuous variable. In addition, we did not observe a significant main effect for rs7530511.The association between a polymorphism in IL12B and psoriasis risk may be modified by measures of overall and central adiposity.
| S-EPMC4179882 | biostudies-literature
Project description:BackgroundPsoriasis (PsO) is a T-cell-associated inflammatory autoimmune dermatitis. Leucine leucine-37 (LL-37) is upregulated in PsO patients and correlated with the area and severity of PsO. However, the exact relation between LL-37 and T cell-associated inflammation is not well understood. It is very important to clarify the relationship between LL-37 and inflammatory response for clinical diagnosis and treatment of PsO. This study investigated the serum levels of LL-37 and inflammatory cytokines, as well as correlations between them in PsO patients, which aimed to provide new ideas for the diagnosis and treatment of PsO.MethodsPsO patients (n = 50) and healthy volunteers (n = 33) were recruited in this study. Skin specimens were stained with hematoxylin and eosin (H&E). The serum levels of LL-37, T-helper type 1 (Th1, IFN-γ), T-helper type 17 (Th17, IL-17), T-helper type 22 (Th22, IL-22), and T-helper type 2 cytokines (Th2, IL-4) were assessed by enzyme-linked immunosorbent assay. Some of the patients were re-recruited after treatment to evaluate LL-37 and cytokines levels.ResultsPathological changes were observed in PsO skin lesions. LL-37, IFN-γ, IL-17, and IL-22 serum levels were much higher in PsO patients than those in healthy volunteers (p < .001), and posttreatment reduction was observed in five patients. However, no remarkable difference in IL-4 level (p > .05) was found. LL-37 level was positively correlated with IFN-γ, IL-17, and IL-22 levels (p < .001) in PsO patients.ConclusionLL-37 expression was significantly associated with inflammatory response, which may provide us new ideas for diagnosing and monitoring disease activity of PsO.
| S-EPMC10013411 | biostudies-literature
Project description:The skin is a peripheral lymphoid organ, being the first immunological defense against infections as the initial interface between the organism and the external background. The maintenance of the skin immune homeostasis depends on a finely equilibrium of well-regulated relations between different cells and exogenous pathogens. Inflammatory skin diseases are directly linked to the dysregulation of this equilibrium. The present review discusses the role of the immune system, of T cells, in the etiopathogenesis of psoriasis, illustrating a potential rationale for innovative therapeutic intervention.
| S-EPMC6773242 | biostudies-literature
Project description:Psoriasis is a chronic and persistent inflammatory skin disease seriously affecting the quality of human life. In this study, we reported an ancient formula of Chinese folk medicine, the natural plant antimicrobial solution (PAMs) for its anti-inflammatory effects and proposed the primary mechanisms on inhibiting the inflammatory response in TNF-?/IFN-?-induced HaCaT cells and imiquimod-induced psoriasis-like skin disease mouse model. Two main functional components of hydroxysafflor Yellow A and allantoin in PAMs were quantified by HPLC to be 94.2±2.2 and 262.9±12.5 ?g/mL respectively. PAMs could significantly reduce the gene expression and inflammatory cytokines production of Macrophage-Derived Chemokine (MDC), IL-8 and IL-6 in TNF-?/IFN-?-induced HaCaT cells. PAMs also significantly ameliorates the psoriatic-like symptoms in a mouse model with the evaluation scores for both the single (scales, thickness, erythema) and cumulative features were in the order of blank control < Dexamethasone < PAMs < 50% ethanol < model groups. The results were further confirmed by hematoxylin-eosin staining, RT-qPCR and immunohistochemistry. The down-regulated gene expression of IL-8, TNF-?, ICAM-1 and IL-23 in mouse tissues was consistent with the results from those of the HaCaT cells. The inhibition of psoriasis-like skin inflammation by PAMs was correlated with the inactivation of the translocation of P65 protein into cellular nucleus, indicating the inhibition of the inflammatory NF-?B signaling pathway. Taken together, these findings suggest that PAMs may be a promising drug candidate for the treatment of inflammatory skin disorders, such as psoriasis.
| S-EPMC5413058 | biostudies-literature