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Transcriptome profiling of lesional skin from Spink5 conditional knock-out mice

ABSTRACT: We generated a viable mouse model of Netherton syndrome by conditional ablation of Spink5 gene in the epidermis. To characterize this model at the molecular level, we induced Spink5 deletion in young adult mice and collected lesional skin samples for transcriptome analyses.

ORGANISM(S): Mus musculus

PROVIDER: GSE224280 | GEO | 2024/02/05

REPOSITORIES: GEO

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Transcriptome profiling of lymph nodes from Spink5 conditional knock-out mice.

Project description:We generated a viable mouse model of Netherton syndrome by conditional ablation of Spink5 gene in the epidermis. To study the systemic inflammation phenotype of this mouse model at the molecular level, we induced Spink5 deletion in the skin of young adult mice and collected inguinal lymph nodes for transcriptome analyses.

2024-02-05 | GSE224409 | GEO

Transcriptome profiling of lesional skin from neonate Spink5 constitutive knock-out mice

Project description:Spink5 constitituve knock-out mice mimic the disease features of Netherton syndrome but die within several hours after birth due to severe skin barrier defect. To characterize the skin barrier and skin inflammation phenotype of this mouse model at the molecular level, we collected back skin samples from mice shortly after their birth.

2024-02-05 | GSE224674 | GEO

Comparative analyses of Netherton syndrome patients and Spink5 conditional knock-out mice define disease-relevant pathways

Project description:Netherton syndrome (NS) is a rare skin disease caused by loss-of-function mutations in the serine peptidase inhibitor Kazal type 5 (SPINK5) gene. Disease severity and the lack of efficacious treatments call for a better understanding of NS mechanisms. Here we describe a viable, Spink5 conditional knock-out (cKO) mouse model, allowing to study NS progression. Using comparative transcriptomics and proteomics, we determine a disease molecular profile conserved in mouse models and NS patients. Spink5 cKO mice and NS patients share skin barrier and inflammation signatures defined by up-regulation of proteases, IL-17, IL-36, IL-20 family cytokines. Furthermore, we show that systemic inflammation in Spink5 cKO mice is associated with thymic atrophy and is driven by innate immunity and IL-17/IL-22 signaling. By comparing skin transcriptomes and proteomes, we uncovered several putative substrates of tissue kallikrein-related proteases (KLKs), demonstrating that KLKs can proteolytically regulate IL-36 pro-inflammatory cytokines. Our study thus provides a conserved molecular framework for NS disease, adding new insights into its mechanisms and therapeutic targets.

2023-02-02 | MSV000091184 | MassIVE

Transcriptome profiling of lesional skin from 3-week-old Tg.hKLK5 mice

Project description:Transgenic mice over-experssing human KLK5 (Tg.hKLK5) in the epidermis develop an inflammatory skin phenotype resembling Netherton syndrome. To characterize the skin inflammation phenotype of this mouse model at the molecular level, we collected back skin samples from young mice at three weeks of age, when the skin phenotype is most severe.

2024-02-05 | GSE224673 | GEO

Transcription profiling by array of epidermal shave samples taken from lesional and non-lesional skin from German atopic dermatitis patients and from healthy skin from German controls

Project description:Epigenetic alterations are increasingly recognized as mechanisms for disease-associated changes in genome function and important risk factors for complex diseases. The epigenome differs between cell types and so far has been characterized in few human tissues only. In order to identify disease-associated DNA methylation differences for atopic dermatitis (AD), we investigated DNA from whole blood, T cells, B cells, as well as lesional and non-lesional epidermis from AD patients and healthy controls. To elicit functional links, we examined epidermal mRNA expression profiles. No genome-wide significant DNA methylation differences between AD cases and controls were observed in whole blood, T cells, and B cells, and, in general, intra-individual differences in DNA methylation were larger than interindividual differences. However, striking methylation differences were observed between lesional epidermis from patients and healthy control epidermis for various CpG sites, which partly correlated with altered transcript levels of genes predominantly relevant for epidermal differentiation and innate immune response. Significant DNA methylation differences were discordant in skin and blood samples, suggesting that blood is not an ideal surrogate for skin tissue. Our pilot study provides preliminary evidence for functionally relevant DNA methylation differences associated with AD, particularly in the epidermis, and represents a starting point for future investigations of epigenetic mechanisms in AD. Total RNA obtained from 7 patients from non-lesional skin, 12 patients from lesional skin and 14 controls from healthy skin

2014-08-26 | E-GEOD-60709 | biostudies-arrayexpress

IL-36 is a hallmark of Netherton syndrome with type I IFN, Th2 and Th9 responses distinguishing its dual clinical manifestations

Project description:Netherton syndrome (NS) is a rare recessive skin disorder caused by loss-of-function mutations in SPINK5 encoding the protease inhibitor LEKTI. NS patients suffer from a severe skin barrier defect, display inflammatory skin lesions and superficial scaling with atopic manifestations. They can present with typical ichthyosis linearis circumflexa (NS-ILC) or scaly erythroderma (NS-SE). Here we employed a combination of several molecular profiling methods to comprehensively characterize the skin, immune cells and allergic phenotypes of NS-ILC and NS-SE patients. This integrated multi-omic approach revealed abnormal epidermal proliferation and differentiation and IL-17/IL-36 signatures in lesional skin and blood in both NS endotypes. While the molecular profiles of NS-ILC and NS-SE lesional skin were very similar, non-lesional skin of each disease subtype displayed distinctive molecular features. NS-SE non-lesional and lesional epidermis showed activation of the type I IFN signaling pathway, which is involved in skin homeostasis and inflammation. NS-ILC lesional skin differed from NS-ILC non-lesional skin by increased complement activation and neutrophil infiltration. Serum cytokine profiling and immunophenotyping of circulating lymphocytes showed a Th2-driven allergic response in NS-ILC, whereas NS-SE patients displayed mainly a Th9 axis with increased CCL22/MDC and CCL17/TARC serum levels. This study identifies IL-17/IL-36 as predominant signaling axes in both NS endotypes and unveils distinct molecular features characterizing NS-ILC and NS-SE. These results identify new therapeutic targets and could pave the way for precision medicine of NS.

2021-12-31 | GSE164285 | GEO

Gene expression in healthy and lesional psoriatic epidermis from human skin biopsies (laser capture microdissection): set 1

Project description:We performed microarray analysis on laser-microdissected epidermis from healthy volunteers and psoriatic patients to identify genes dysregulated in lesional psoriatic epidermis

2017-06-14 | GSE68923 | GEO

Gene expression in healthy and lesional psoriatic epidermis from human skin biopsies (laser capture microdissection): set 2

2017-06-14 | GSE68937 | GEO

Comparative miRNA expression of normal skin from control and lesional skin from mice

Project description:The efficacy of monoclonal antibodies against either interleukin (IL)-17 or the IL-17 receptor in psoriasis therapy provides strong evidence that IL-17 is the major inflammatory mediation in this disease. However, how IL-17 induces epidermal hyperplasia in psoriasis remains largely unknown. Here, we show that IL-17 actives NF-kB in keratinocytes and initiates the NF-kB-dependent transcription of microRNA-31 (miR-31), one of the most abundant microRNAs in the epidermis of lesional skin of psoriasis and two related mouse models. Similar to IL-17 deficiency (IL-17-/-), knocking out miR-31 (miR-31-/-) or targeting it by antagomir-31 prevents keratinocytes Ki67 expression and inhibits acanthosis and dermal inflammation in psoriasis mouse model. Moreover, PPP6c, a negative regulator restricting G0/G1 to G2/M phase progression in the cell cycle, is diminished in human psoriatic epidermis and is directly targeted by miR-31. Inhibition of ppp6c is functionally important for the biological effects of miR-31 in the development of epidermal hyperplasia. Thus, our data define IL-17-inducede miR-31 and its target ppp6c as critical factors for hyperproliferative epidermis in psoriasis. Epidermis samples from affected ears derived from 3 CD18hypo PL/J mice (DIS) or normal ears derived from 3 CD18hypo C57BL/6J mice(2128) were used for RNA extraction and hybridization on Affymetrix microarrays. We sought to compare miRNA expression of normal skin from control and lesional skin.

2013-12-31 | E-GEOD-50099 | biostudies-arrayexpress

Transcription profiling by array of epidermal shave samples taken from lesional and non-lesional skin from German atopic dermatitis patients and from healthy skin from German controls

2014-08-26 | GSE60709 | GEO

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