Effects of TSLP challenge on airway inflammation in naïve and OVA-sensitized mice
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE41667 | GEO | 2015/10/11
SECONDARY ACCESSION(S): PRJNA177908
REPOSITORIES: GEO
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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
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.
2016-03-26 | GSE79596 | GEO
Project description:Chlorella has been reported to have various physiological activities, including antiarteriosclerotic, cholesterol-lowering, anti-inflammatory, and immunoregulatory effects. However, there has been no report on the long-term effects of chlorella ingestion on immunity. In the present study, 4- to 10-week-old (young) and 4- to 50-week-old (old) female BALB/c mice were sensitized or not with ovalbumin (OVA), and given basic diet containing chlorella powder at 2% or basic diet alone. The effects of chlorella ingestion on immunity were investigated by measurement of splenic cytokines and immunoglobulin (Ig), analysis of T- and B-cells in the spleen and small intestine by flow cytometry, and analysis of the liver by DNA microarray. Results were compared between the young and old, OVA-sensitized and -nonsensitized, and chlorella and non-chlorella ingestion groups. Production of interferon-γ (IFN-γ) was maintained in the nonsensitized old groups, and ratios of T-helper type 1 (Th1) to T-helper type 2 (Th2) cells were similar in the young and old groups. In addition, overproduction of OVA-specific Igs due to OVA sensitization was strongly suppressed, and significant immunotolerance was exhibited irrespective of age. In addition, suppression of T-cell decreases in the spleen due to aging and suppression of changes in T- and B-cells due to OVA sensitization in the small intestinal lymph were demonstrated on flow cytometric analyses. On DNA microarray analysis, immune-related terms including IL11 and major histocompatibility complex (MHC) class 1 were detected, and expression of genes was shown, which were related to IL1-linked genes and complex involving macrophages from the pathways of cytokines and inflammatory response. In addition, suppressions of declined lipid metabolism and energy production were also suggested. Although how the ingredients in chlorella were involved in these changes is unclear, our findings suggest that prevention of decrease in acquired immunity by aging and induction of strong immunotolerance occurred following chlorella ingestion. The Young Control group and Old Control group were fed normal food, and the Old Chlorella intake group was fed food including 2.0% Chlorella powder. The total RNA was isolated from liver and samples was pooled for each group (n = 6 for each group). A table of normalized log2 ratios (where numerator is sample expression data, and denominator is all sample median data) is linked below as a supplementary file.
2010-11-16 | E-GEOD-19032 | biostudies-arrayexpress
Project description:Chlorella has been reported to have various physiological activities, including antiarteriosclerotic, cholesterol-lowering, anti-inflammatory, and immunoregulatory effects. However, there has been no report on the long-term effects of chlorella ingestion on immunity. In the present study, 4- to 10-week-old (young) and 4- to 50-week-old (old) female BALB/c mice were sensitized or not with ovalbumin (OVA), and given basic diet containing chlorella powder at 2% or basic diet alone. The effects of chlorella ingestion on immunity were investigated by measurement of splenic cytokines and immunoglobulin (Ig), analysis of T- and B-cells in the spleen and small intestine by flow cytometry, and analysis of the liver by DNA microarray. Results were compared between the young and old, OVA-sensitized and -nonsensitized, and chlorella and non-chlorella ingestion groups. Production of interferon-γ (IFN-γ) was maintained in the nonsensitized old groups, and ratios of T-helper type 1 (Th1) to T-helper type 2 (Th2) cells were similar in the young and old groups. In addition, overproduction of OVA-specific Igs due to OVA sensitization was strongly suppressed, and significant immunotolerance was exhibited irrespective of age. In addition, suppression of T-cell decreases in the spleen due to aging and suppression of changes in T- and B-cells due to OVA sensitization in the small intestinal lymph were demonstrated on flow cytometric analyses. On DNA microarray analysis, immune-related terms including IL11 and major histocompatibility complex (MHC) class 1 were detected, and expression of genes was shown, which were related to IL1-linked genes and complex involving macrophages from the pathways of cytokines and inflammatory response. In addition, suppressions of declined lipid metabolism and energy production were also suggested. Although how the ingredients in chlorella were involved in these changes is unclear, our findings suggest that prevention of decrease in acquired immunity by aging and induction of strong immunotolerance occurred following chlorella ingestion.
2010-11-16 | GSE19032 | GEO
Project description:Challenge with ovalbumin antigen is a common model for asthma in mice. We sought to identify the gene expression differences in lung tissue in naïve and OVA-sensitized mice, in response to OVA challenge.
2015-10-11 | GSE41665 | GEO
Project description:Atopic dermatitis is a multifactorial allergic skin disease in humans and dogs. Genetic predisposition, immunologic hyperreactivity, a defective skin barrier and environmental factors play a role in its pathogenesis. The aim of this study was to analyze gene expression in the skin of dogs sensitized to house dust mite antigens. Skin biopsies were collected from six sensitized and six non-sensitized Beagle dogs from normal, non-treated skin before and six and 24 hours after challenge using skin patches with allergen or saline as a negative control. Transcriptome analysis was performed by the use of DNA microarrays and expression of selected genes was validated by quantitative real-time RT-PCR. Expression data was compared between groups (unpaired design). After 24 hours 597 differentially expressed genes were detected, 361 with higher and 226 with lower mRNA concentration in allergen treated skin of sensitized dogs compared to their saline-treated skin and compared to the control specimens. Functional annotation clustering, pathway-and co-citation analysis showed, that the genes with increased expression were involved in inflammation, wound healing and immune response. In contrast, genes with decreased expression in sensitized dogs were associated with differentiation and barrier function of the skin. As the sensitized dogs did not show differences in the untreated skin compared to controls, inflammation after allergen patch test probably led to a decrease in the expression of genes important for barrier formation. Our results further confirm the similar pathophysiology of human and canine atopic dermatitis and revealed genes previously not known to be involved in canine atopic dermatitis. 60 canine (dog) skin tissue samples; six sensitized and six non-sensitized Beagle dogs; samples collected before (0h), 6h and 24h after challenge with allergen; samples collected from a skin area treated with saline and from an area treated with allergen
2014-09-23 | E-GEOD-58442 | biostudies-arrayexpress
Project description:Atopic dermatitis is a multifactorial allergic skin disease in humans and dogs. Genetic predisposition, immunologic hyperreactivity, a defective skin barrier and environmental factors play a role in its pathogenesis. The aim of this study was to analyze gene expression in the skin of dogs sensitized to house dust mite antigens. Skin biopsies were collected from six sensitized and six non-sensitized Beagle dogs from normal, non-treated skin before and six and 24 hours after challenge using skin patches with allergen or saline as a negative control. Transcriptome analysis was performed by the use of DNA microarrays and expression of selected genes was validated by quantitative real-time RT-PCR. Expression data was compared between groups (unpaired design). After 24 hours 597 differentially expressed genes were detected, 361 with higher and 226 with lower mRNA concentration in allergen treated skin of sensitized dogs compared to their saline-treated skin and compared to the control specimens. Functional annotation clustering, pathway-and co-citation analysis showed, that the genes with increased expression were involved in inflammation, wound healing and immune response. In contrast, genes with decreased expression in sensitized dogs were associated with differentiation and barrier function of the skin. As the sensitized dogs did not show differences in the untreated skin compared to controls, inflammation after allergen patch test probably led to a decrease in the expression of genes important for barrier formation. Our results further confirm the similar pathophysiology of human and canine atopic dermatitis and revealed genes previously not known to be involved in canine atopic dermatitis.
2014-09-23 | GSE58442 | GEO
Project description:Thymic stromal lymphopoietin (TSLP) is a key player in the pathogenesis of atopic diseases. Its pathophysiological relevance has sparked great interest in therapeutically targeting TSLP. Yet, so far, no small-mo lecule TSLP inhibitors exist due to the challenging nature of disrupting the protein-protein interaction between TSLP and its receptor. Here, we report the development of small-molecule TSLP receptor inhibitors using structure- based virtual screening and docking of >1,000,000 compounds followed by iterative chemical synthesis. BP79 emerged as our lead compound that effectively abrogates TSLP-triggered cytokine release at low micromolar concentrations. Topical application of BP79 yields efficient skin absorption followed by significant downregulation of atopy-relevant proinflammatory cytokines in immunocompetent skin disease models. For further analysis, we developed a human atopic disease drug discovery platform using microfluidic multi-organ chips. Here, topical application of BP79 onto atopic-like skin disease models that were co -cultivated with lung models in the presence of Th2 cells effectively suppressed immune cell infiltration and key atopy mediators including IL-13, IL-4, TSLP, and periostin, while upregulating skin barrier prote ins such as filaggrin. RNA-Seq analysis corroborated these findings and also indicated protective downstream effects on the lung epithelium. To the best of our knowledge, this represents the first report of a po tent and safe small molecule TSLPR inhibitor which has the potential to expand the therapeutic and preventive options in atopic diseases. Further, it serves as a starting point for further developments in target ing TSLP as a central player of inflammation.
2024-05-17 | GSE264457 | GEO
Project description:Lungs from miR-21+/+ and miR-21-/- mice sensitized with OVA/Alum and challenged with either saline or OVA.
2011-08-25 | E-MEXP-3119 | biostudies-arrayexpress
Project description:Background: How prenatal smoke exposure affects DNA methylation leading to atopic disorders remains to be addressed. Epigenetic biomarkers informative of prenatal smoke exposure and atopic disorders are wanting. Since most children suffering from atopic dermatitis (AD) continue to develop asthma later in life, we explored whether prenatal smoke exposure e induces DNA methylation and searched for predictive epigenetic biomarkers for smoke related atopic disorders. Methods: Methylation differences associated with smoke exposure were screened by Illumina methylation panel for children from the Taiwan birth panel study cohort initially. Information about development of atopic dermatitis (AD) and risk factors were collected. Cord blood cotinine levels were measured to represent prenatal smoke exposure. CpG loci that demonstrated a statistically significant difference in methylation were validated by methylation-dependent fragment separation (MDFS). Differential methylation in three genes (TSLP, GSTT1, and CYB5R3) was identified through the screen and their functions were investigated. Results: Among these, only thymic stromal lymphopoietin (TSLP) gene displayed significant difference in promoter methylation percentage after being validated by MDFS (p=0.029). TSLP gene was further investigated in a larger sample of 92 children from the cohort. Methylation status of the TSLP 5′-CpG island (CGI) was found to be significantly associated with prenatal smoke exposure (OR=3.59, 95%CI=1.49-8.64; cotinine level 0.10 ng/ml, sensitivity= 77%; specificity = 61%) and with AD (OR=4.77, 95%CI=1.47-15.53). The degree of TSLP 5′CGI methylation inversely correlated with TSLP protein expression levels (per unit: β=－6.69 ng/ml; 95% CIs, －12.80~－0.59; p=0.032). Conclusions: The effect of prenatal tobacco smoke exposure on the risk for AD may be mediated through DNA methylation. Cord blood methylated TSLP 5′CGI may be a potential epigenetic biomarker for environmentally-related atopic disorders. The buffy coat and plasma samples were separated and stored at −80°C. DNA (100 ng-500 ng) was extracted from cord white blood cells. Microarrays have been performed to investigate fourteen samples, which were classified as two groups according to cotinine exposure dosage (7 versus 7 : high exposure verses low exposure).
2013-12-31 | E-GEOD-35222 | biostudies-arrayexpress