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Topical vitamin D3 and low-calcemic analogs induce thymic stromal lymphopoietin in mouse keratinocytes and trigger an atopic dermatitis.

ABSTRACT: We have demonstrated that cytokine thymic stromal lymphopoietin (TSLP), whose expression is rapidly induced upon keratinocyte-selective ablation of retinoid X receptors (RXRs) -alpha and -beta in the mouse (RXRalphabeta(ep-/-) mice), plays a key role in initiating a skin and systemic atopic dermatitis-like phenotype. We show here that topical application of the physiologically active ligand [1alpha,25-(OH)(2)D(3); calcitriol] of the vitamin D receptor, or of its low-calcemic analog MC903 (calcipotriol; Dovonex), induces TSLP expression in epidermal keratinocytes, which results in an atopic dermatitis-like syndrome mimicking that seen in RXRalphabeta(ep-/-) mutants and transgenic mice overexpressing TSLP in keratinocytes. Furthermore, topical application of retinoic acid receptor RARgamma-selective agonist BMS961 also induces TSLP expression either on its own or synergistically with 1alpha,25-(OH)(2)D(3). Our data demonstrate that RXR/vitamin D receptor and RXR/retinoic acid receptor-gamma heterodimers and their ligands cell-autonomously control the expression of TSLP in epidermal keratinocytes of the mouse. We propose molecular mechanisms through which vitamin D3 and retinoic acid signalings could be involved in the pathogenesis of atopic diseases.

SUBMITTER: Li M

PROVIDER: S-EPMC1544239 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Retinoid X receptor ablation in adult mouse keratinocytes generates an atopic dermatitis triggered by thymic stromal lymphopoietin.

Project description:To investigate the role of retinoid X receptors (RXRs) in epidermal homeostasis, we generated RXRalphabeta(ep-/-) somatic mutants in which both RXRalpha and RXRbeta are selectively ablated in epidermal keratinocytes of adult mice. These mice develop a chronic dermatitis mimicking that observed in atopic dermatitis (AD) patients. In addition, they exhibit immunological abnormalities including elevated serum levels of IgE and IgG, associated with blood and tissue eosinophilia, indicating that keratinocyte-selective ablation of RXRs also generates a systemic syndrome similar to that found in AD patients. Furthermore, the profile of increased expression of cytokines and chemokines in skin of keratinocyte-selective RXRalphabeta-ablated mutants was typical of a T helper 2-type inflammation, known to be crucially involved in human AD pathogenesis. Finally, we demonstrate that thymic stromal lymphopoietin, whose expression is rapidly and strongly induced in RXRalphabeta-ablated keratinocytes, plays a key role in initiating the skin and systemic AD-like pathologies.

| S-EPMC1253602 | biostudies-literature

Association between fine mapping thymic stromal lymphopoietin and atopic dermatitis onset and persistence.

Project description:BACKGROUND:Atopic dermatitis (AD) is a common chronic relapsing skin disease. Genetic variants have been associated with skin barrier function and immune regulation. Thymic stromal lymphopoietin (TSLP), an immune regulator, has been previously associated with AD. OBJECTIVE:To fine map TSLP and evaluate associations with the onset and persistence of AD. METHODS:TSLP variation was determined using targeted massively parallel sequencing in a longitudinal cohort of children with AD. Evaluations included linkage disequilibrium and the persistence of AD for as many as 10 years of follow-up. The association between the presence of AD and rs1898671 variation was evaluated in a second independent cohort. RESULTS:The minor variant frequency for rs1898671 was 23.5% (95% CI, 21.4%-25.8%). This variant was not in linkage disequilibrium with other TSLP variants in the longitudinal cohort (n = 741). White children with AD were less likely to have rs1898671 variant (odds ratio [OR], 1.41; 95% CI, 1.20-1.66) than Genome Aggregation Database controls. Children with AD and the rs1898671 variant during follow-up were more likely to have remission than children who were wild type for rs1898671 (OR, 1.56; 95% CI, 1.26-1.91). In the second cohort (n = 585), the rs1898671 variant was less prevalent in those with AD than those without. The protective effect was greater in rs1898671 heterozygotes (OR, 1.91; 95% CI, 1.34-2.75) than homozygotes (OR, 1.28; 95% CI, 0.61-2.70). CONCLUSION:TSLP and specifically rs1898671 are important in the pathogenesis of AD and could represent a potential clinical target for the development of therapies to treat individuals with AD.

| S-EPMC6878172 | biostudies-literature

Thymic stromal lymphopoietin variation, filaggrin loss of function, and the persistence of atopic dermatitis.

Project description:ImportanceAtopic dermatitis (AD) is a common chronic illness of childhood.ObjectiveTo evaluate the association between thymic stromal lymphopoietin (TSLP) variation and the persistence of skin symptoms of AD.Design, setting, and participantsA prospective cohort study was conducted in the general community. Participants included 796 children enrolled in the Pediatric Eczema Elective Registry. EXPOSURE Evaluation of TSLP variation.Main outcomes and measuresSelf-reported outcome of whether a child's skin had no symptoms of AD and required no medications for 6 months at 6-month intervals.ResultsWe evaluated 14 variants of TSLP. The variant rs1898671 was significantly associated with the outcome in white children (P = .01). As measured by overlapping CIs, similar odds ratios (ORs) were noted among whites (OR, 1.72; 95% CI, 1.11-2.66) and African Americans (1.33; 0.52-3.45). Further within the subcohort of individuals with a filaggrin protein (FLG) loss-of-function mutation, those with TSLP variation were more likely to have less-persistent disease (OR, 4.92; 95% CI, 2.04-11.86).Conclusions and relevanceThe TSLP variation is associated with less persistent AD. Therefore, TSLP may be a potential therapeutic target for the treatment of AD, especially in individuals with diminished barrier function due to FLG mutations. This is an attractive hypothesis that can be tested in clinical trials.

| S-EPMC4414492 | biostudies-literature

ΔNp63 controls a TLR3-mediated mechanism that abundantly provides thymic stromal lymphopoietin in atopic dermatitis.

Project description:In the skin lesions of atopic dermatitis (AD), keratinocytes release large quantities of thymic stromal lymphopoietin (TSLP), causing unfavorable inflammation along with skin damage. Nevertheless, how TSLP influences keratinocytes themselves is still unknown. In this study, we showed that ΔNp63, a p53-homologue, predominantly expressed in keratinocytes regulated the receptor complex of TSLP, which determines susceptibility to self-derived TSLP. Expression of TSLP receptors in skin tissues and keratinocytes was assessed by immunohistochemistry and quantitative RT-PCR, and in vitro studies were also performed to examine the functional relevance of ΔNp63 in the expression of TSLP receptors and the constituting autocrine and/or paracrine pathway of TSLP under the condition of stimuli to innate receptors sensing cell damage. The results showed that normal keratinocytes in the upper epidermis preferentially expressed TSLP receptors and conversely lacked ΔNp63, which has an inhibitory effect on the expression of TSLP receptors. Interestingly, the epidermis of AD lesions was found to abundantly contain keratinocytes with low or undetectable levels of ΔNp63 (ΔNp63(lo/-)). Moreover, in the absence of ΔNp63, keratinocytes readily presented TSLP and other cytokines by stimuli through Toll-like receptor 3 (TLR3). Together with the evidence that extrinsic TSLP itself augments TSLP production by keratinocytes without ΔNp63, the results indicate that ΔNp63(lo/-) keratinocytes generate TSLP through a putative autocrine and/or paracrine pathway upon TLR3 stimulation within AD lesions, since moieties of damaged cells and pathogens stimulate TLR3.

| S-EPMC4149429 | biostudies-literature

Kallikrein 5 induces atopic dermatitis-like lesions through PAR2-mediated thymic stromal lymphopoietin expression in Netherton syndrome.

Project description:Netherton syndrome (NS) is a severe genetic skin disease with constant atopic manifestations that is caused by mutations in the serine protease inhibitor Kazal-type 5 (SPINK5) gene, which encodes the protease inhibitor lymphoepithelial Kazal-type-related inhibitor (LEKTI). Lack of LEKTI causes stratum corneum detachment secondary to epidermal proteases hyperactivity. This skin barrier defect favors allergen absorption and is generally regarded as the underlying cause for atopy in NS. We show for the first time that the pro-Th2 cytokine thymic stromal lymphopoietin (TSLP), the thymus and activation-regulated chemokine, and the macrophage-derived chemokine are overexpressed in LEKTI-deficient epidermis. This is part of an original biological cascade in which unregulated kallikrein (KLK) 5 directly activates proteinase-activated receptor 2 and induces nuclear factor kappaB-mediated overexpression of TSLP, intercellular adhesion molecule 1, tumor necrosis factor alpha, and IL8. This proinflammatory and proallergic pathway is independent of the primary epithelial failure and is activated under basal conditions in NS keratinocytes. This cell-autonomous process is already established in the epidermis of Spink5(-/-) embryos, and the resulting proinflammatory microenvironment leads to eosinophilic and mast cell infiltration in a skin graft model in nude mice. Collectively, these data establish that uncontrolled KLK5 activity in NS epidermis can trigger atopic dermatitis (AD)-like lesions, independently of the environment and the adaptive immune system. They illustrate the crucial role of protease signaling in skin inflammation and point to new therapeutic targets for NS as well as candidate genes for AD and atopy.

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Topical tacrolimus for atopic dermatitis.

Project description: Not available

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Polyinosinic:polycytidylic acid aggravates calcipotriol-induced atopic dermatitis-like skin lesions in mice by increasing the expression of thymic stromal lymphopoietin.

Project description:BackgroundPolyinosinic:polycytidylic acid [poly (I:C)] is a synthetic viral double-stranded RNA analog that can activate Toll-like receptor 3 (TLR3) and induce the release of thymic stromal lymphopoietin (TSLP). TSLP has been shown to contribute to atopic dermatitis (AD). This study explored the effects of poly (I:C) in a calcipotriol-induced model of murine AD.MethodsCalcipotriol (MC903) was used to establish AD-like mice model. Mice in the MC903 + poly (I:C) group were then treated with poly (I:C) in a concentration of 5 µg/g bodyweight. The impact of poly (I:C) treatment on these animals was assessed based upon changes in lesions, bodyweight, ear thickness, and histopathological findings. In addition, serum interleukin 4 (IL-4), interferon-γ (IFN-γ), immunoglobulin E (IgE), IL-13, and TSLP levels were measured using enzyme-linked immunosorbent assay (ELISA), while tissue IL-13 and TSLP levels were assessed using ELISA, Western blotting, and immunohistochemical staining, and mast cell infiltration was assessed through toluidine blue (TBO) staining.ResultsRelative to vehicle control treatment, poly (I:C) administration was associated with a significant exacerbation of calcipotriol-induced AD-like murine skin lesions. In animals treated with poly (I:C), the levels of serum IL-4, IL-13 and TSLP increased significantly, while the level of IFN-γ did not change. It also increased IL-13 and TSLP levels in skin lesions relative to the control-group mice and increased dermal mast cell infiltration and IgE production.ConclusionsThese data indicate that poly (I:C) treatment and exogenous activation of TLR3 exacerbate murine calcipotriol-induced AD-like skin lesions in part by increasing the production of TSLP and other T-helper 2 (Th2)-related cytokines.KeywordsAtopic dermatitis (AD); polyinosinic:polycytidylic acid [poly (I:C)]; thymic stromal lymphopoietin (TSLP); Toll-like receptor 3 (TLR3).

| S-EPMC8908153 | biostudies-literature

Thymic stromal lymphopoietin overproduced by keratinocytes in mouse skin aggravates experimental asthma.

Project description:Atopic dermatitis (AD) is often the initial step in the "atopic march," given that more than half of AD patients with moderate to severe AD develop asthma later in life. Both AD and asthma share a similar "atopy" phenotype that includes T helper type 2 inflammation with eosinophilia and hyper-IgE immunoglobulinemia, but the molecular mechanisms underlying the "atopic march" remain elusive. In the present study, we show that induced expression of thymic stromal lymphopoietin (TSLP) in mouse epidermal keratinocytes upon topical application of MC903 (a low calcemic analogue of vitamin D3) not only triggers AD as we previously reported but also aggravates experimental allergic asthma induced by ovalbumin sensitization and challenge. Our study, which provides a mouse model to study human "atopic march," indicates that keratinocyte-produced TSLP may represent an important factor in the link of atopic dermatitis to asthma.

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Process utilities for topical treatment in atopic dermatitis.

Project description:PurposeManagement of atopic dermatitis (AD) typically requires application of topical treatments, often multiple times a day. The cosmetic properties and burdensome application of these treatments can be detrimental to quality of life (QoL). Patients who achieve good disease control through use of systemic therapies may reduce the frequency and amount of topical applications, improving QoL. This study aimed to quantify the utility and disutility for topical AD treatment processes.MethodsSeven vignettes describing different skincare regimens for people with moderate-to-severe AD were developed with input from healthcare professionals. 484 respondents from the general population completed time trade-off items for each vignette. Utility values for each regimen, and disutilities associated with the impact of changes to skincare regimens, were calculated. Analysis of variance assessed differences between skincare regimens.ResultsAs skincare regimens increased in intensity (0.7968 for the most intense; 0.9999 for the least), utility values decreased. There were no statistically significant differences between skincare regimens followed by patients with good disease control (0.9862 to 0.9999); however, when compared to those involving topical corticosteroids and emollient combinations (0.7968 to 0.8835), significant differences were observed (p < 0.001). The largest disutilities (0.1521 to 0.1705) were between skincare regimens describing the use of topical corticosteroids plus emollient and those followed by patients with good disease control.ConclusionsThe application of topical treatments has a detrimental effect on QoL, which increases with the duration and frequency of applications. Further research is needed to investigate how health and process utilities interact and both can be integrated into medical decision-making.

| S-EPMC6698259 | biostudies-literature

mRNA expression of Atopic Dermatitis keratinocytes

Project description:mRNA array analysis of total RNA from primary kertinocytes from three healthy controls, three atopic dermatitis patients and three psoriasis patients was carried out

2012-06-01 | E-MTAB-728 | biostudies-arrayexpress

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