Subpopulations of CD163 positive macrophages are classically activated in psoriasis
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE18686 | GEO | 2010/03/01
SECONDARY ACCESSION(S): PRJNA121567
REPOSITORIES: GEO
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Project description:The success of TNF inhibitors for treatment of psoriasis and other inflammatory diseases was previously attributed to blockade of innate immunity. In a clinical trial using etanercept TNF blocking agent to treat psoriasis vulgaris, we used affymetrix gene arrays to analyze broad gene profiles in lesional skin at multiple timepoints during drug treatment (baseline, and weeks 1, 2, 4 and 12) compared to non-lesional skin. This analysis created a temporal model of TNF-dependent gene regulation that informs molecular mechanisms of TNF-mediated inflammation. We identified four gene clusters that were differentially down-modulated during etanercept treatment: the cluster down-regulated most rapidly contained mostly dendritic cell activation genes. Culturing human keratinocytes with TNF, IFNg and IL-17 generated a list of keratinocyte genes regulated by each cytokine. The IL-17 pathway genes were strongly down-modulated early, whereas IFNg pathway genes were not down-modulated until final disease resolution at week 12. Finally, we show that TNF blockade rapidly inhibits IL-12/IL-23 p40 subunit expression, and that p40 neutralization inhibits psoriatic dermal emigre-mediated Th17 polarization. We hypothesize that etanercept inhibits myeloid dendritic cell production of IL-23, a Th17 survival cytokine, resulting in rapid downregulation of IL-17 pathway genes. This data links effects of TNF blockade on the innate immune system with the adaptive immune system. Experiment Overall Design: In this study 15 patients with moderate-to-severe psoriasis were given 50mg of etanercept (Amgen) biweekly for 12 weeks. And analyzed using gene array on mRNA extracted from tissue collected at each biopsy time point (non-lesional Time: 0; lesional Time: 0, weeks 1, 2, 4, and 12). Patients were stratified as 'responders' or 'non-responders' based on whether or not they achieved histologic disease resolution by week 12 of etanercept treatment (decreased epidermal thickening, normalization of proliferation marker Ki67, and loss of differentiation marker K16).
2009-11-09 | E-GEOD-11903 | biostudies-arrayexpress
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:The success of TNF inhibitors for treatment of psoriasis and other inflammatory diseases was previously attributed to blockade of innate immunity. In a clinical trial using etanercept TNF blocking agent to treat psoriasis vulgaris, we used affymetrix gene arrays to analyze broad gene profiles in lesional skin at multiple timepoints during drug treatment (baseline, and weeks 1, 2, 4 and 12) compared to non-lesional skin. This analysis created a temporal model of TNF-dependent gene regulation that informs molecular mechanisms of TNF-mediated inflammation. We identified four gene clusters that were differentially down-modulated during etanercept treatment: the cluster down-regulated most rapidly contained mostly dendritic cell activation genes. Culturing human keratinocytes with TNF, IFNg and IL-17 generated a list of keratinocyte genes regulated by each cytokine. The IL-17 pathway genes were strongly down-modulated early, whereas IFNg pathway genes were not down-modulated until final disease resolution at week 12. Finally, we show that TNF blockade rapidly inhibits IL-12/IL-23 p40 subunit expression, and that p40 neutralization inhibits psoriatic dermal émigré-mediated Th17 polarization. We hypothesize that etanercept inhibits myeloid dendritic cell production of IL-23, a Th17 survival cytokine, resulting in rapid downregulation of IL-17 pathway genes. This data links effects of TNF blockade on the innate immune system with the adaptive immune system. Keywords: time-course experiment
2009-10-30 | GSE11903 | GEO
Project description:Scalp psoriasis shows a variable clinical spectrum and in many cases poses a great therapeutic challenge. However, it remains unknown whether the immune response of scalp psoriasis differs from understood pathomechanisms of psoriasis on other skin areas. We sought to determine the cellular and mollecular phenotype of scalp psoriasis by performing a comparative analysis of scalp vs skin using lesional and nonlesional samples from 20 Caucasian subjects with untreated moderate to severe psoriasis and significant scalp involvement, and 10 control subjects without psoriasis. Our results suggest that even in the scalp psoriasis is a disease of the inter-follicular skin. The immune mechanisms that mediate scalp psoriasis were found to be similar to those involved in skin psoriasis. However, the magnitude of dysregulation, number of differentially expressed genes, and enrichment of the psoriatic genomic fingerprinting were more prominent in skin lesions. Furthermore, the scalp transcriptome showed increased modulation of several gene-sets, particularly those induced by interferon-gamma, compared with skin psoriasis which was mainly associated with activation of TNFâµ/L-17/IL-22-induced keratinocyte response genes. We also detected differences in expression of gene-sets involving negative regulation, epigenetic regulation, epidermal differentiation, and dendritic cell or Th1/Th17/Th22-related T-cell processes. To define the transcriptomic profile of scalp skin, punch biopsies (6 mm diameter) were obtained from 20 Caucasian patients with untreated moderate to severe psoriasis with significative scalp involvement and 10 control subjects without psoriasis (N). Lesional (LS) samples were isolated from the infiltrated border of a plaque of psoriasis. Non lesional (NL) samples were taken from scalp areas with no visible psoriasis between the infiltrated plaques.
2015-11-25 | E-GEOD-75343 | biostudies-arrayexpress
Project description:Macrophages are important cells of the innate immune system, and their study is essential to gain greater understanding of the inflammatory nature of psoriasis. We used immunohistochemistry and double-label immunofluorescence to characterize CD163(+) macrophages in psoriasis. Dermal macrophages were increased in psoriasis compared with normal skin and were identified by CD163, RFD7, CD68, lysosomal-associated membrane protein 2 (LAMP2), stabilin-1, and macrophage receptor with collagenous structure (MARCO). CD163(+) macrophages expressed C-lectins CD206/macrophage mannose receptor and CD209/DC-SIGN, as well as costimulatory molecules CD86 and CD40. They did not express mature dendritic cell (DC) markers CD208/DC-lysosomal-associated membrane glycoprotein, CD205/DEC205, or CD83. Microarray analysis of in vitro-derived macrophages treated with IFN-? showed that many of the genes upregulated in macrophages were found in psoriasis, including STAT1, CXCL9, Mx1, and HLA-DR. CD163(+) macrophages produced inflammatory molecules IL-23p19 and IL-12/23p40 as well as tumor necrosis factor (TNF) and inducible nitric oxide synthase (iNOS). These data show that CD163 is a superior marker of macrophages, and identifies a subpopulation of "classically activated" macrophages in psoriasis. We conclude that macrophages are likely to contribute to the pathogenic inflammation in psoriasis, a prototypical T helper 1 (Th1) and Th17 disease, by releasing key inflammatory products.
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Project description:Purpose: profiling the differential transcripts usage in HACN treated macrophage polarization toward proinflammatory M1 polarization Methods: transcriptome analysis by the RNA-seq via mRNA pull-down Results: The mRNA profiles by RNA sequencing in bone marrow-derived macrophages showed that the whole gene expression patterns altered by lipopolysaccharide (LPS) were restored by HACN pre-treatment, and most of those genes were related to the inflammatory response including M1 polarization Conclusions: The inhibitory effects of HA-NPs on LPS-induced M1 polarization are attributed to the presence of self-assembled HA shell, not the hydrophobic constituents and the free HAs.
2023-11-21 | GSE189361 | GEO
Project description:To understand the mechanism of disease progression in psoriasis, we defined Asian small plaque psoriasis (small psoriasis) and Asian intermediate plaque psoriasis (intermediate psoriasis) as psoriasis subtypes with limited disease progression, and compared their cellular and molecular signatures with the classic subtype of Western large plaque psoriasis (large psoriasis; GSE30999). Transcriptome analyses in pre-treatment skin biopsies from patients with Asian small and intermediate plaque psoriasis. 12 Asian small plaque psoriasis skin biopsy tissues (7 lesional and 5 non-lesional skin) and 15 Asian intermediate plaque psoriasis skin biopsy tissues (7 lesional and 8 non-lesional skin). GCRMA (using gcrma package from R/Bioconductor) and adjusted for batch effect. The expression data was combined with Western large psoriasis (GSE30999). Using a normalization based upon quantiles, the expression data was normalized based upon a specified normalization distribution of GSE30999 (see publication for GSE67853). The complete dataset representing: (1) 12 Asian small plaque psoriasis Samples, (2) 15 Asian intermediate plaque psoriasis Samples, and (3) 130 Western large plaque psoriasis Samples from GSE30999 (re-processed), is linked below as a supplementary file.
2016-01-10 | E-GEOD-67853 | biostudies-arrayexpress
Project description:Biopsies from uninvolved and from lesional skin of 13 patients with plaque-type psoriasis. Based on paired samples, 179 genes were more than 2-fold differentially expressed in lesional skin. Experiment Overall Design: Comparative RNA expression profiles from uninvolved and lesional skin of 13 patients with mild to severe plaque-type psoriasis.
2008-11-07 | E-GEOD-6710 | biostudies-arrayexpress
Project description:We used microarry to charactarize differences in gene expression between lesional and non-lesional psoriasis skin. Our hypothethis was that IL-37 is downregulated in psoriasis.
2022-06-07 | GSE161683 | GEO
Project description:We observed robust overexpression of type I interferon (IFN)-inducible genes and genomic signatures that indicate T cell and dendritic cell infiltration in lesional skin. Up-regulation of mRNAs for IFN-a subtypes was observed in lesional skin compared with nonlesional skin. Enrichment of mature dendritic cells and 2 type I IFN-inducible proteins, STAT1 and ISG15, were observed in the majority of lesional skin biopsies. Concordant overexpression of IFN-c and TNF-a inducible gene signatures occurred at the same disease sites. Experiment Overall Design: A total of 82 Affymetrix HGU133 Plus arrays were run on 54 total subjects. This includes: skin biopsy samples from 21 normal healthy donors (Normal-1 to Normal-21), 56 skin biopsy samples from 28 psoriasis patients who had match lesional and uninvolved (non-lesional) tissue (NS-1/LS-1 to NS-9/LS-9, NS-11/LS-11 to NS-14/LS-14, and NS-16/LS-16 to NS-30/LS-30), and 5 samples from psoriasis patients that only provided lesional skin biopsies (LS-10, LS-15, and LS-31 to LS-33).
2009-03-01 | E-GEOD-14905 | biostudies-arrayexpress