Expression data from skin of mice treated subcutaneously with TGF-beta, IL-13 or TSLP for 7 days
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
SUBMITTER: Romy Christmann
PROVIDER: E-GEOD-34297 | biostudies-arrayexpress |
REPOSITORIES: biostudies-arrayexpress
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Project description:Gene expression in mice skin stimulated with 3 different cytokines We used microarrays to detail the global programme of specific or common gene expression by 3 cytokines: TGF-beta, IL-13 and TSLP
2013-10-31 | GSE34297 | 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:The ontogeny of human Langerhans cells (LCs) remains poorly characterized, in particular the nature of LC precursors and the factors that may drive LC differentiation. Through a systematic transcriptomic analysis of TSLP-activated dendritic cells (DCs), we unexpectedly identified markers that have been associated with a skin-homing potential as well as with a LC phenotype. We performed transcriptomic analysis of TSLP-activated blood DCs, as compared to freshly purified, Medium-, and TNF-activated DCs. Among TSLP up-regulated genes, we identified molecules associated with skin homing, LC phenotype, and LC function, as determined by a literature-based survey. Conversely, genes not expressed in LCs were not found among TSLP-induced genes. Further experiments showed that TGF-? synergized with TSLP leading to the differentiation of blood BDCA-1+ DCs into bona fide Birbeck granule-positive LCs. The ontogeny of human Langerhans cells (LCs) remains poorly characterized, in particular the nature of LC precursors and the factors that may drive LC differentiation. Through a systematic transcriptomic analysis of TSLP-activated dendritic cells (DCs), we unexpectedly identified markers that have been associated with a skin-homing potential as well as with a LC phenotype. We performed transcriptomic analysis of TSLP-activated blood DCs, as compared to freshly purified, Medium-, and TNF-activated DCs. Among TSLP up-regulated genes, we identified molecules associated with skin homing, LC phenotype, and LC function, as determined by a literature-based survey. Conversely, genes not expressed in LCs were not found among TSLP-induced genes. Further experiments showed that TGF-? synergized with TSLP leading to the differentiation of blood BDCA-1+ DCs into bona fide Birbeck granule-positive LCs. Dendritic cells (DC) were purified from the blood of healthy human donors. Each replicate comes from a different donor. There are 6 freshly purified samples (Control_0h), 4 DC samples cultured during 6h with no additional stimulus than the medium (Control_6h), 5 samples cultured during 6h with recombinant TSLP (Thymic Stromal Lymphopoietin at 20 ng/uL) (TSLP_6h) and 3 samples cultured during 6h with recombinant TNF (Tumor necrosis factor at 20 ng/mL) (TNF_6h).
2014-08-01 | E-GEOD-59237 | biostudies-arrayexpress
Project description:Thymic stromal lymphopoietin (TSLP) is a type I cytokine that plays a central role in induction of allergic inflammatory responses. Its principal targets have been reported to be dendritic cells and / or CD4 T cells; epithelial cells are a principal source. We report here the development of a reporter mouse (TSLP-ZsG) in which a ZsGreen (ZsG)-encoding construct has been inserted by recombineering into a bacterial artificial chromosome (BAC) immediately at the translation initiating ATG of TSLP. The expression of ZsG by mice transgenic for the recombinant BAC appears to be a faithful surrogate for TSLP expression, particularly in keratinocytes and medullary thymic epithelials cells (mTECs). A comparison of gene expression in ZsG expressing and ZsG negative mTECs and cortical thymic epithelial cells, which are all ZsG negative, revealed that all three populations can be distinguished from one another. In particular ZsG (and TSLP) expressing mTECs and ZsG- mTECs are separable populations based on gene expression profiling. Little or no expression of ZsG is observed in bone marrow-derived mast cells or basophils or in CD45+ cells infiltrating TSLP/ZsG-expressing skin. Using the TSLP-ZsG reporter mouse, we show that TNFa and IL-4/IL-13 are potent inducers of TSLP expression by keratinocytes and that local activation of Th2 and Th1 cells induces keratinocyte TSLP expression. We suggest that the capacity of TSLP to both induce Th2 differentiation and to be induced by activated Th2 cells raises the possibility that TSLP may be involved in a positive feedback loop to enhance allergic inflammatory conditions.
2015-01-06 | GSE54343 | GEO
Project description:The ontogeny of human Langerhans cells (LCs) remains poorly characterized, in particular the nature of LC precursors and the factors that may drive LC differentiation. Through a systematic transcriptomic analysis of TSLP-activated dendritic cells (DCs), we unexpectedly identified markers that have been associated with a skin-homing potential as well as with a LC phenotype. We performed transcriptomic analysis of TSLP-activated blood DCs, as compared to freshly purified, Medium-, and TNF-activated DCs. Among TSLP up-regulated genes, we identified molecules associated with skin homing, LC phenotype, and LC function, as determined by a literature-based survey. Conversely, genes not expressed in LCs were not found among TSLP-induced genes. Further experiments showed that TGF-β synergized with TSLP leading to the differentiation of blood BDCA-1+ DCs into bona fide Birbeck granule-positive LCs. The ontogeny of human Langerhans cells (LCs) remains poorly characterized, in particular the nature of LC precursors and the factors that may drive LC differentiation. Through a systematic transcriptomic analysis of TSLP-activated dendritic cells (DCs), we unexpectedly identified markers that have been associated with a skin-homing potential as well as with a LC phenotype. We performed transcriptomic analysis of TSLP-activated blood DCs, as compared to freshly purified, Medium-, and TNF-activated DCs. Among TSLP up-regulated genes, we identified molecules associated with skin homing, LC phenotype, and LC function, as determined by a literature-based survey. Conversely, genes not expressed in LCs were not found among TSLP-induced genes. Further experiments showed that TGF-β synergized with TSLP leading to the differentiation of blood BDCA-1+ DCs into bona fide Birbeck granule-positive LCs.
2014-08-01 | GSE59237 | GEO
Project description:Staphylococcus aureus can cause serious skin, respiratory, and other life-threatening invasive infections in humans, and methicillin-resistant S. aureus (MRSA) strains have been acquiring increasing antibiotic resistance. While MRSA was once mainly considered a hospital-acquired infection, the emergence of new strains, some of which are pandemic, has resulted in community-acquired MRSA infections that often present as serious skin infections in otherwise healthy individuals. Accordingly, defining the mechanisms that govern the activation and regulation of the immune response to MRSA is clinically important and could lead to the discovery of much needed rational targets for therapeutic intervention. Because the cytokine thymic stromal lymphopoetin (TSLP) is highly expressed by keratinocytes of the skin3, we investigated its role in host-defense against MRSA. Here we demonstrate that TSLP acts on neutrophils to increase their killing of MRSA. In particular, we show that both mouse and human neutrophils express functional TSLP receptors. Strikingly, TSLP enhances mouse neutrophil killing of MRSA in both an in vitro whole blood killing assay and an in vivo skin infection model. Similarly, TSLP acts directly on purified human blood neutrophils to reduce MRSA burden. Unexpectedly, we demonstrate that TSLP mediates these effects both in vivo and in vitro by engaging the complement C5 system. Thus, TSLP increases MRSA killing in a neutrophil- and complement-dependent manner, revealing a key connection between TSLP and the innate complement system, with potentially important therapeutic implications for control of MRSA infection.
2016-11-18 | GSE73313 | GEO
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:The cytokine TSLP stimulates in vitro proliferation of human fetal B cell progenitors. Genetic alterations that cause overexpression of the TSLP receptor component, CRLF2, lead to B cell acute lymphoblastic leukemia (CRLF2 B-ALL) with poor outcome. The in vivo role of TSLP in normal human B cell development and its contribution to CRLF2 B-ALL are unknown. In classic xenograft models CRLF2-mediated signaling is unlikely to be activated by mouse TSLP, based on data from engineered cellular models. Here, we show that mouse TSLP does not induce activation of the CRLF-2 downstream pathways (JAK/STAT and AKT/mTOR) that are induced by human TSLP (hTSLP) in CRLF2 B-ALL cells. Based on this, we developed a novel human-mouse xenograft model system comprised of mice that produce hTSLP (+T mice) to activate human CRLF2-mediated signaling and mice that lack hTSLP (–T mice). Normal serum levels of hTSLP were achieved in +T mice, while hTSLP was undetectable in –T mice. hTSLP produced by stroma induced JAK/STAT and AKT/mTOR pathway activation and showed functional in vivo effects on normal human B cell progenitors and primary CRLF2 B-ALL cells. Whole genome microarray of primary CRLF2 B-ALL showed an induction of mTOR regulated gene expression and preservation of TSLP responsiveness in cells expanded in +T mice as compared to –T mice.
2016-05-03 | GSE65274 | GEO
Project description:Regulatory T cells are indispensable for the immune homeostasis. Recent studies revealed the crucial roles of tissue factors; however, the roles of epithelial cell derived cytokine TSLP in the maturation of regulatory T cells are not adressed. Here, we report that TSLP activates mTOR signaling to mature regulatory T cells to maintain large intestine homeostasis.
2023-01-27 | GSE189713 | GEO