MAS-related GPR family member X2-mediated mast cell activation promotes early inflammatory reaction in psoriasis
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo Sapiens
SUBMITTER: 
Songmei Geng
PROVIDER: PXD047735 | iProX | Tue Dec 12 00:00:00 GMT 2023
REPOSITORIES: iProX
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Project description:Psoriasis is a common chronic inflammatory skin disease. Keratinocytes (KCs) are important effector cells that can recruit inflammatory cells by releasing inflammatory factors and chemokines to promote the inflammatory cascade in psoriasis. However, the mechanism underlying KC activation in psoriasis remains unclear. Livin is an inhibitor of apoptotic proteins and its expression can directly affect the proliferation and metastasis of tumor cells. Livin expression has been reported to be significantly increased in the lesions of patients with psoriasis; however, its specific role in KC activation has not yet been reported. The aim of this study was to investigate whether livin regulates KC activation and causes the release of inflammatory mediators. The expression levels of livin in patients with psoriasis, an imiquimod (IMQ) mouse model, and M5-treated HaCaT cells were determined via immunofluorescence staining, reverse transcription-quantitative polymerase chain reaction, enzyme-linked immunosorbent assay (ELISA), and western blotting. We constructed livin knockdown (Knockdown-HaCaT) and negative control (NC-HaCaT) cells using human immunodeficiency virus-1-based lentiviral vectors to study the function of livin in KCs via RNA-sequencing and proteomics analysis. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses were performed. Moreover, the effect of livin expression on the release of inflammatory mediators in KCs was verified using ELISA.
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Project description:Inverse and erythrodermic psoriasis are rare subtypes of psoriasis. Whereas the former is characterized by shiny erythematous non-scaly plaques in the body folds, the latter has widespread redness with fine scale, covering over 80% of the body-surface area, and can be life-threatening. Both are considered to be clinical subtypes of chronic plaque psoriasis, and often co-exist or evolve from plaque psoriasis (Boyd and Menter, 1989; Omland and Gniadecki, 2015), but the pathogenic mechanisms involved are unknown, and current treatments are frequently unsatisfactory. To assess shared and unique processes between chronic plaque, inverse, and erythrodermic psoriasis we analyzed archived formalin-fixed paraffin-embedded biopsies of clinically and histologically confirmed chronic plaque (n=12), inverse (n=40) and erythrodermic psoriasis cases (n=30) and healthy control skin (n=20) using Affymetrix ST 2.1 Arrays. Compared with healthy skin, psoriatic plaque lesions yielded 2450 differentially expressed genes (DEGs) (FDR, p<0.05), inverse psoriasis lesions yielded 408 DEGs (FDR, p<0.05) and erythrodermic psoriasis lesions yielded 447 DEGs (FDR, p<0.05). In total 294 genes were found to be shared among the three disease subtypes (FDR, p<0.05). While the overlap only accounted for 12% of the DEGs in chronic plaque psoriasis, it accounted for 66% and 72% of DEGs in erythrodermic and inverse psoriasis respectively.
2017-01-27 | GSE83582 | GEO
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:Background: Previous work has identified CD11c+CD1c- dendritic cells (DCs) as the major 'inflammatory' dermal DC population in psoriasis vulgaris and CD1c+ DCs as the 'resident' cutaneous DC population. Objective: To further define molecular differences between these two myeloid dermal DC populations. Methods: Inflammatory and resident DCs were single-cell sorted from psoriasis lesional skin biopsies, and gene array expression profiling was performed. Results were confirmed with RT-PCR, flow cytometry, immunohistochemistry, and double label immunofluorescence. Pooled human keratinocytes were cultured for functional studies. Results: TNF-related apoptosis-inducing ligand (TRAIL), Toll-like receptors (TLRs) 1 and 2, S100A12/EN-RAGE, CD32, and many other inflammatory products were selectively expressed in inflammatory DCs than in resident DCs. Flow cytometry and immunofluorescence confirmed higher protein expression on CD1c- versus CD1c+ DCs. TRAIL receptor, death receptor 4 (DR4), was expressed on basal keratinocytes and blood vessels, and in vitro culture of keratinocytes with rh-TRAIL induced CCL20 leukocyte chemokine. Conclusion: CD11c+CD1c- inflammatory DCs in psoriatic lesional skin express a wide range of inflammatory molecules compared to skin resident CD1c+ DCs. Some molecules made by inflammatory DCs, including TRAIL, could have direct effects on keratinocytes or other skin cell types to promote disease pathogenesis. Shave biopsies were cultured overnight in dispase to remove the epidermis. Dermis was cultured for 36-48 hours to obtain dermal single cell suspensions. These cells were stained with HLA-DR, CD11c, BDCA-1 (DCs) and FACS-sorted into HLA-DR+11c+BDCA-1+, HLA-DR+11c+BDCA-1- populations into Trizol. RNA was extracted and processed for microarray. 2 dependent groups.
2010-06-08 | E-GEOD-20264 | biostudies-arrayexpress
Project description:Background: Previous work has identified CD11c+CD1c- dendritic cells (DCs) as the major ”inflammatory” dermal DC population in psoriasis vulgaris and CD1c+ DCs as the “resident” cutaneous DC population. Objective: To further define molecular differences between these two myeloid dermal DC populations. Methods: Inflammatory and resident DCs were single-cell sorted from psoriasis lesional skin biopsies, and gene array expression profiling was performed. Results were confirmed with RT-PCR, flow cytometry, immunohistochemistry, and double label immunofluorescence. Pooled human keratinocytes were cultured for functional studies. Results: TNF-related apoptosis-inducing ligand (TRAIL), Toll-like receptors (TLRs) 1 and 2, S100A12/EN-RAGE, CD32, and many other inflammatory products were selectively expressed in inflammatory DCs than in resident DCs. Flow cytometry and immunofluorescence confirmed higher protein expression on CD1c- versus CD1c+ DCs. TRAIL receptor, death receptor 4 (DR4), was expressed on basal keratinocytes and blood vessels, and in vitro culture of keratinocytes with rh-TRAIL induced CCL20 leukocyte chemokine. Conclusion: CD11c+CD1c- inflammatory DCs in psoriatic lesional skin express a wide range of inflammatory molecules compared to skin resident CD1c+ DCs. Some molecules made by inflammatory DCs, including TRAIL, could have direct effects on keratinocytes or other skin cell types to promote disease pathogenesis.
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