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Induction of inflammatory cytokines by a keratin mutation in a mouse model for EBS

ABSTRACT: Epidermolysis bullosa simplex (EBS) is a skin disorder caused by mutations in keratin (K) 5 or K14 genes. It is widely regarded as a mechanobullous disease, resulting from a weakened cytoskeleton, causing extensive cytolysis. It was postulated by others that certain K14 mutations induce TNF-alfa and increase apoptosis. Here, we report that in K5-/- mice , the mRNA and protein levels of TNF-alfa remain unaltered. Transcriptome analysis of K5-/- mice revealed however, that the pro-inflammatory cytokines interleukin-6 and interleukin-1beta were significantly upregulated at the mRNA level in K5-/- mouse skin. These results were confirmed by TaqMan real-time PCR and ELISA assays. We hypothesize that keratin mutations contribute to EBS in a mouse model by inducing local inflammation that mediates a stress response. Keywords: comparative gene expression profile

ORGANISM(S): Mus musculus

PROVIDER: GSE7663 | GEO | 2007/05/01

SECONDARY ACCESSION(S): PRJNA99743

REPOSITORIES: GEO

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Transcription profiling of mouse model of Epidermolysis bullosa simplex (EBS) K5-/- skin reveals induction of inflammatory cytokines by a keratin mutation

Project description:Epidermolysis bullosa simplex (EBS) is a skin disorder caused by mutations in keratin (K) 5 or K14 genes. It is widely regarded as a mechanobullous disease, resulting from a weakened cytoskeleton, causing extensive cytolysis. It was postulated by others that certain K14 mutations induce TNF-alfa and increase apoptosis. Here, we report that in K5-/- mice , the mRNA and protein levels of TNF-alfa remain unaltered. Transcriptome analysis of K5-/- mice revealed however, that the pro-inflammatory cytokines interleukin-6 and interleukin-1beta were significantly upregulated at the mRNA level in K5-/- mouse skin. These results were confirmed by TaqMan real-time PCR and ELISA assays. We hypothesize that keratin mutations contribute to EBS in a mouse model by inducing local inflammation that mediates a stress response. Experiment Overall Design: Two groups were K5-/- skin and wildtype . Six animals were included in each group. All the total RNA samples were isolated from tissues taken immediately after birth, and were pooled for later microarray experiments. Using realtime PCR and ELISA analysis confirmed our microarray result.

2008-06-15 | E-GEOD-7663 | biostudies-arrayexpress

A compound-based therapy approach for epidermolysis bullosa simplex (EBS)

Project description:Keratin cytoskeletal proteins are crucial for the maintenance of skin integrity. Mutations in genes coding for K5 and K14 cause the human skin disorder epidermolysis bullosa simplex (EBS) leading to substantial alterations in keratin assembly and collapse of keratin filaments into cytoplasmic protein aggregates. The phenotypic consequences of K5 and K14 mutations comprise fragility of basal keratinocytes and skin blistering upon mild mechanical trauma. Treatment of EBS is only supportive and consists primarily of wound care and avoidance of mechanical stress. Besides symptomatic care, no efficient therapeutic treatment is available for EBS. In the present study, we used patient-derived keratinocytes carrying the most frequent K14.R125C mutation as a reproducible EBS model to understand EBS pathomechanisms and to develop a therapy approach aimed to restore a functional keratin network. Numerous post-translational modifications (PTMs) such as phosphorylation have been reported to occur on keratins, which affect the organization of keratin networks. Whether keratin mutations affect the occurrence of PTMs and thereby keratin aggregation in EBS is yet unknown. We find that the K14.R125C mutation alters keratin and keratin-associated protein PTMs in distinct ways and suggest that disease mutations and altered PTMs aggravate keratin aggregation. We reason that chemical compounds affecting the interplay of mutations and PTMs enable the reformation of a keratin cytoskeleton from aggregates are potential candidates for combating EBS.

2022-06-29 | PXD030939 | Pride

Dowling-Meara experiment 2

Project description:Dowling-Meara type epidermolysis bullosa simplex (EBS-DM) is a severe blistering disease, caused by dominant mutations in either the keratin-5 (K5) or keratin-14 (K14) gene. K5 and K14 are the major components of the intermediate filament (IF) network in basal keratinocytes. Due to the dominant nature of EBS-DM, misfolded K5 or K14 proteins are incorporated into intermediate filaments, rendering them sensitive to mechanical stress. Upon trauma, these filaments disrupt and the keratinocytes lyse, leading to intra-epidermal blistering.The dominant nature of K5 and K14 mutations in EBS-DM represents a challenge to gene-therapeutic approaches. Therefore, we investigated the gene expression profile of a K14 mutant keratinocyte cell line (EBDM1) and compared it to the gene expression profile of a wild-type keratinocyte cell line (NEB1). The aim of this study was to identify differentially regulated genes as potential therapeutic targets for the development of new therapies.

2013-07-23 | E-MTAB-1641 | biostudies-arrayexpress

Dowling-Meara experiment 1

Project description:Dowling-Meara type epidermolysis bullosa simplex (EBS-DM) is a severe blistering disease, caused by dominant mutations in either the keratin-5 (K5) or keratin-14 (K14) gene. K5 and K14 are the major components of the intermediate filament (IF) network in basal keratinocytes. Due to the dominant nature of EBS-DM, misfolded K5 or K14 proteins are incorporated into intermediate filaments, rendering them sensitive to mechanical stress. Upon trauma, these filaments disrupt and the keratinocytes lyse, leading to intra-epidermal blistering. The dominant nature of K5 and K14 mutations in EBS-DM represents a challenge to gene therapeutic approaches. Therefore, we investigated the gene expression profile of a K14 mutant keratinocyte cell line (KEB7) and compared it to the gene expression profile of a wild-type keratinocyte cell line (NEB1). The aim of this study was to identify differentially regulated genes as potential therapeutic targets for the development of new therapies.

2013-07-23 | E-MTAB-1640 | biostudies-arrayexpress

Gene expression profile after doxycycline treatment in keratin5 knockout epidermis

Project description:Epidermolysis bullosa simplex (EBS) is a skin disorder caused by mutations in keratin (K) 5 or K14 genes. Little effect therapy is available.Following clinical reports, we applied the small molecule doxycycline to K5-/- mice. We demonstrate that doxycycline extended the survival of neonatal K5-/- mice from less than 1 to up to 8 hours. Microarray and TaqMan real-time PCR showed a downregulation of MMP-13 and IL-1beta, indicating an effect of doxycycline on transcription. Our data offer a novel small molecule based therapy approach for EBS. Keywords: drug treatment, global gene expression comparative profile

2007-05-01 | GSE7662 | GEO

Transcription profiling of mouse model of Epidermolysis bullosa simplex keratin5 knockout epidermis response to doxycycline treatment

Project description:Epidermolysis bullosa simplex (EBS) is a skin disorder caused by mutations in keratin (K) 5 or K14 genes. Little effect therapy is available.Following clinical reports, we applied the small molecule doxycycline to K5-/- mice. We demonstrate that doxycycline extended the survival of neonatal K5-/- mice from less than 1 to up to 8 hours. Microarray and TaqMan real-time PCR showed a downregulation of MMP-13 and IL-1ï¢, indicating an effect of doxycycline on transcription. Our data offer a novel small molecule based therapy approach for EBS. Experiment Overall Design: doxycycline (50 Âµg/mlwith 5 % sucrose) was administered by oral route to pregnant K5+/- females (mated to K5+/- males) starting from E13.5. 5 % sucrose solution was administered to the control group.

2008-06-15 | E-GEOD-7662 | biostudies-arrayexpress

Human iPS-derived-keratinocytes, a new useful model to identify and explore pathological phenotype of Epidermolysis Bullosa Simplex.

Project description:Epidermolysis Bullosa Simplex (EBS), an autosomal dominant skin disorder, is characterized by trauma-induced skin fragility. Genetically, majority of cases are related to missense mutations in two keratin genes, KRT5 or KRT14, leading to cytolysis of basal keratinocytes and intraepidermal blistering. Only symptomatic treatment exists for EBS patients so far. Progress towards identification of new treatments have been hampered by incomplete understanding of the mechanisms underlying this disease, and availability of relevant and reliable in vitro models recapitulating the physiopathological mechanisms. Recent advances in stem cell field have fueled the prospect that these limitations could be overcome thanks to the availability of disease-specific human induced pluripotent stem cells (hiPSC). Here we generated hiPSC-derived keratinocytes from EBS patients carrying KRT5 dominant mutations and compared them to non-affected hiPSC-derived keratinocytes as well as their primary counterparts. Our results demonstrated that EBS hiPSC-derived keratinocytes displayed proliferative defects, increased capacity to migrate, alteration of ERK signaling pathway and cytoplasmic keratin filament aggregates in response to osmotic-shock treatment in a pattern similar to primary EBS keratinocytes. Of interest, EBS hiPSC-derived keratinocytes exhibited a downregulation of hemidesmosomal proteins revealing the different effects of KRT5 mutations on keratin cytoskeletal organization. Combination of culture miniaturization and treatment with the chaperone molecule 4-Phenybutiric acid (4-PBA), our results demonstrated that hiPSC-derived keratinocytes represent a suitable model for identifying novel therapies for EBS.

2022-04-04 | GSE196116 | GEO

Effects of 4-phenylbutyrate on human keratinocytes

Project description:Keratins 5 and 14 are critical for cytoskeletal integrity, as shown by missense mutations in these genes, which cause the severe skin fragility disorder epidermolysis bullosa simplex (EBS). The complexity of the pathomechanisms in EBS is not fully understood and no effective management exists. In addition to fragility, EBS keratinocytes are characterized by aggregates of misfolded keratin. Here, we tested the chemical chaperone 4-phenylbutyrate (4-PBA) as a putative novel therapy, using keratinocytes from patients with severe generalized EBS due to distinct KRT5 and KRT14 mutations.

2019-12-03 | PXD010028 | Pride

Gene expression profiling of infrequently and frequently dividing cells in the mouse epidermis

Project description:Infrequently (LRCs) and frequently (non-LRCs) dividing cells in the mouse epidermis are moleculary distinct. Fluorescence activated cell sorting (FACS) from back skin cells of quadruple-transgenic mice harboring K5-tTA, pTRE-H2B-GFP, K14-CreER and Rosa-tdTomato transgenes.

2016-09-01 | E-GEOD-70523 | biostudies-arrayexpress

Keratin-dependent TSLP expression suggests a link between skin blistering and atopic disease

Project description:Atopic dermatitis (AD) is a pruritic and inflammatory disorder characterized by elevated levels of thymic stromal lymphopoietin (TSLP). Pruritus is prevalent in epidermolysis bullosa (EB). Currently, epidermal barrier disruption is known to trigger TSLP upregulation, however, mechanisms controlling TSLP expression remain incompletely understood. Tslp levels were highly upregulated in the epidermis and in the serum of keratin-deficient mice. Cultured keratinocytes either lacking keratins or expressing the dominant K14p.Arg131Pro show highly increased TSLP. Re-expression of wild-type K14 normalized TSLP levels. We demonstrate that keratins regulate Tslp expression in parts through MEK1/2 activation. The finding that 8 out of 17 EBS patients show elevated TSLP serum levels supports a major role of keratins in TSLP regulation. Our data identify a novel, keratin-dependent and cell-intrinsic regulation of Tslp. Elevated TSLP levels likely explain the high prevalence of pruritus in EBS and additional forms of EB, suggesting TSLP as novel biomarker for pruritus in EB. MEK1/2, in addition to calcineurin inhibitors, might be suitable drugs to treat itch in EB. Investigation was carried out using Keratin deficient keratinocytes isolated from typeI keratin mice.

2016-03-26 | E-GEOD-79596 | biostudies-arrayexpress

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