Environmental factors transmitted by aryl hydrocarbon receptor influence severity of psoriatic skin inflammation
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
SUBMITTER: Gitta Stockinger
PROVIDER: E-GEOD-47965 | biostudies-arrayexpress |
REPOSITORIES: biostudies-arrayexpress
Publications
Activation of the aryl hydrocarbon receptor dampens the severity of inflammatory skin conditions.
Di Meglio Paola P Duarte João H JH Ahlfors Helena H Owens Nick D L ND Li Ying Y Villanova Federica F Tosi Isabella I Hirota Keiji K Nestle Frank O FO Mrowietz Ulrich U Gilchrist Michael J MJ Stockinger Brigitta B
Immunity 20140605 6
Environmental stimuli are known to contribute to psoriasis pathogenesis and that of other autoimmune diseases, but the mechanisms are largely unknown. Here we show that the aryl hydrocarbon receptor (AhR), a transcription factor that senses environmental stimuli, modulates pathology in psoriasis. AhR-activating ligands reduced inflammation in the lesional skin of psoriasis patients, whereas AhR antagonists increased inflammation. Similarly, AhR signaling via the endogenous ligand FICZ reduced th ...[more]
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Project description:Environmental stimuli are known to contribute to psoriasis pathogenesis and that of other autoimmune diseases, but the mechanism is unknown. Here we show that the aryl hydrocarbon receptor (AhR), a transcription factor that senses environmental stimuli, modulates pathology in psoriasis. AhR-activating ligands reduced inflammation in the lesional skin of psoriasis patients, whereas AhR antagonists upregulated inflammation. Similarly, AhR signaling via the endogenous FICZ ligand reduced the inflammatory response in the imiquimod-induced model of psoriasis and AhR deficient mice exhibited a substantial exacerbation of the disease, compared to AhR sufficient controls. Non-haematopoietic cells, in particular keratinocytes, were responsible for this hyper-inflammatory response, which involved increased reactivity to IL-1beta and upregulation of AP-1 family members of transcription factors. Thus, our data suggest a critical role for AhR in the regulation of inflammatory responses and open the possibility for novel therapeutic strategies in chronic inflammatory disorders. Total RNA obtained from skin explants taken from psoriatic patients or healthy donors cultured in the presence of AhR agonist or antagonist
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Project description:Background: Plaque psoriasis is a chronic autoimmune disorder characterized by the development of red scaly plaques. To date psoriasis lesional skin transcriptome has been extensively studied, whereas only few proteomic studies of psoriatic skin are available. Aim: The aim of this study was to compare protein expression patterns of lesional and normally looking skin of psoriasis patients with skin of the healthy volunteers, reveal differentially expressed proteins and identify changes in cell metabolism caused by the disease. Methods: Skin samples of normally looking and lesional skin donated by psoriasis patients (n = 5) and samples of healthy skin donated by volunteers (n = 5) were analyzed by liquid chromatography-tandem mass spectrometry (LC-MS/MS). After protein identification and data processing, the set of differentially expressed proteins was subjected to protein ontology analysis to characterize changes in biological processes, cell components and molecular functions in the patients' skin compared to skin of the healthy volunteers. Results: The performed analysis identified 405 and 59 differentially expressed proteins in lesional and normally looking psoriatic skin compared to healthy control. We discovered decreased expression of KNG1, APOE, HRG, THBS1 and PLG in normally looking skin of the patients. Presumably, these changes were needed to protect the epidermis from spontaneous activation of kallikrein-kinin system and delay the following development of inflammatory response. In lesional skin, we identified several large groups of proteins with coordinated expression. Mainly, these proteins were involved in different aspects of protein and RNA metabolism, namely ATP synthesis and consumption; intracellular trafficking of membrane-bound vesicles, pre-RNA processing, translation, chaperoning and degradation in proteasomes/immunoproteasomes. Conclusion: Our findings explain the molecular basis of metabolic changes caused by disease in skin lesions, such as faster cell turnover and higher metabolic rate. They also indicate on downregulation of kallikrein-kinin system in normally looking skin of the patients that would be needed to delay exacerbation of the disease.
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Project description:Blood (mRNA and miRNA) and skin mRNA transcriptomes were investigated across three time-points in a pilot investigation of ten severe psoriasis patients, treated with the tumor necrosis factor (TNF) inhibitor, etanercept. We used illumina RNA-sequencing to analyse the small-RNA transcriptome in blood
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Project description:mRNA array analysis was carried out using total RNA of skin biopsies from lesional and non-lesional skin of three atopic dermatitits patients and four healthy individuals.
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Project description:Gene expression has been proposed as an intermediate phenotype that can increase power in complex trait gene-mapping studies. Psoriasis, an immune-mediated, inflammatory and hyperproliferative disease of the skin and joints, provides an ideal model system to evaluate this paradigm, as conclusive evidence demonstrates that psoriasis has a genetic basis and the disease tissue is readily accessible. To better understand the complex nature of processes in psoriasis, we characterize gene expression profiles in uninvolved and involved skin from affected individuals as well as normal skin from control individuals. Experiment Overall Design: We extracted total RNA from punch biopsies taken from 58 psoriatic patients and 64 normal healthy controls. Two biopsies were taken from each patient; one 6mm punch biopsy was obtained from lesional skin of each patient (involved sample) and the other from non-lesional skin (uninvolved sample), taken at least 10 cm away from any active plaque. One biopsy was obtained from each healty control. Totally 180 samples were run on Affymetrix HU133 Plus 2.0 microarrays containing >54,000 gene probes. Experiment Overall Design: The raw data from 180 microarrays were processed using the Robust Multichip Average (RMA) method. The expression values in the table were after adjustment of RMA expression values (on the log scale) to account for batch and sex effects. Experiment Overall Design: Definition of abbreviations used in Sample records: NN = normal skin from controls; PN = uninvolved skin from cases; PP = involved skin from cases.
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Project description:Donor-matched human skin biopsies were taken from non-lesional (NL) and lesional skin of positive patch-test reactions to nickel at 24h, 48h, and 120h post allergen application, respectively, and bulk RNA-seq was performed.
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Project description:Background: In present study we performed whole transcriptome analysis in plaque psoriasis patients and compared lesional skin with non-lesional skin and with the skin from healthy controls. We sequenced total RNA from 12 lesional (LP), 12 non-lesional (NLP) and from 12 normal (C) skin biopsies. Results: Compared with previous gene expression profiling studies we had three groups under analysis - LP, NLP and C. Using NLP samples allows to see the transcriptome of visually normal skin from psoriasis patient. In LP skin S100A12, S100A7A, LCE3E, DEFB4A, IL19 were found up regulated. In addition to already well-described genes, we also found several other, not so widely recognized transcripts, related to psoriasis. Namely, KLK9, OAS2, OAS3, PLA2G, IL36G, IL36RN were found to be significantly and consistently related to the psoriatic lesions. Ingenuity pathway analysis was used to define functional networks significantly enriched in the studied samples. The genes up-regulated in the LP samples were related to the innate immunity, IL17 and IL10 networks. In NLP samples innate immunity and IL17 network were activated, but activation of IL10 network was not evident. The transcriptional changes characteristic in the NLP samples can be considered as a molecular signature of “dormant psoriasis”. Conclusions: Taken together, our study described the transcriptome profile characteristic for LP and NLP psoriatic skin. RNA profile of the NLP skin is in between the lesional and healthy skin, with its own specific pattern. We found that both LP and NLP have up-regulated IL17 network, whereas LP skin has up regulated IL10 related cytokines (IL19, IL20, IL24). Moreover, IL36G and IL36RN were identified as strong regulators of skin pathology in both LP and NLP skin samples, with stronger influence in LP samples. 36 samples, 24 from psoriasis and 12 from controls
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Project description:Psoriasis is a chronic inflammatory skin disease characterized by marked proliferation of keratinocytes leading to pronounced epidermal hyperplasia, elongation of rete ridges and hyperkeratosis. The most common form of psoriasis, chronic plaque psoriasis (Psoriasis vulgaris), involves relatively stable occurrence and progression of sharply demarcated lesions, usually on the trunk and extremities, which share a combination of trademark histological features, including tortuous and dilated dermal capillaries, loss of the epidermal granular layer, and accumulation of neutrophils beneath parakeratotic scale. In this study, whole-genome transcriptional profiling was used to characterize gene expression in 4 lesional and uninvolved skin samples obtained from patients with stable chronic plaque psoriasis. Skin mRNA expression was analysed by microarray. Four individuals with chronic plaque psoriasis were enrolled. 6 mm punch biopsies were obtained under local anaesthesia (lidocaine) from uninvolved skin and a target plaque.
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