TSLP expression in the skin is mediated via RAR-RXR pathways

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Transcriptomic and lipidomic profiling of eicosanoid/docosanoid signalling in affected and non-affected skin of human atopic dermatitis patients

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Regulation of retinoid-mediated signaling involved in skin homeostasis by RAR and RXR agonists/antagonists in mouse skin.

Endogenous retinoids like all-trans retinoic acid (ATRA) play important roles in skin homeostasis and skin-based immune responses. Moreover, retinoid signaling was found to be dysregulated in various skin diseases. The present study used topical application of selective agonists and antagonists for retinoic acid receptors (RARs) α and γ and retinoid-X receptors (RXRs) for two weeks on mouse skin in order to determine the role of retinoid receptor subtypes in the gene regulation in skin. We observed pronounced epidermal hyperproliferation upon application of ATRA and synthetic agonists for RARγ and RXR. ATRA and the RARγ agonist further increased retinoid target gene expression (Rbp1, Crabp2, Krt4, Cyp26a1, Cyp26b1) and the chemokines Ccl17 and Ccl22. In contrast, a RARα agonist strongly decreased the expression of ATRA-synthesis enzymes, of retinoid target genes, markers of skin homeostasis, and various cytokines in the skin, thereby markedly resembling the expression profile induced by RXR and RAR antagonists. Our results indicate that RARα and RARγ subtypes possess different roles in the skin and may be of relevance for the auto-regulation of endogenous retinoid signaling in skin. We suggest that dysregulated retinoid signaling in the skin mediated by RXR, RARα and/or RARγ may promote skin-based inflammation and dysregulation of skin barrier properties

Clinical efficacy of omalizumab in chronic spontaneous urticaria is associated with a reduction of FcεRI-positive cells in the skin

Background. Treatment with omalizumab, a humanized recombinant monoclonal anti-IgE antibody, results in clinical efficacy in patients with Chronic Spontaneous Urticaria (CSU). The mechanism of action of omalizumab in CSU has not been elucidated in detail. Objectives. To determine the effects of omalizumab on levels of high affinity IgE receptor-positive (FcεRI+) and IgE- positive (IgE+) dermal cells and blood basophils. Treatment efficacy and safety were also assessed. Study design. In a double-blind study, CSU patients aged 18‑75 years were randomized to receive 300 mg omalizumab (n=20) or placebo (n=10) subcutaneously every 4 weeks for 12 weeks. Changes in disease activity were assessed by use of the weekly Urticaria Activity Score (UAS7). Circulating IgE levels, basophil numbers and levels of expression of FcεRI+ and IgE+ cells in the skin and in blood basophils were determined. Results. Patients receiving omalizumab showed a significantly greater decrease in UAS7 compared with patients receiving placebo. At Week 12 the mean difference in UAS7 between treatment groups was -14.82 (p=0.0027), consistent with previous studies. Total IgE levels in serum were increased after omalizumab treatment and remained elevated up to Week 12. Free IgE levels decreased after omalizumab treatment. Mean levels of FcεRI+ skin cells in patients treated with omalizumab 300 mg were decreased at Week 12 compared with baseline in the dermis of both non-lesional and lesional skin, reaching levels comparable with those seen in healthy volunteers (HVs). There were no statistically significant changes in mean FcɛRI+ cell levels in the placebo group. Similar results were seen for changes in IgE+ cells, although the changes were not statistically significant. The level of peripheral blood basophils increased immediately after treatment start and returned to Baseline values after the follow-up period. The levels of FcεRI and IgE expression on peripheral blood basophils were rapidly reduced by omalizumab treatment up to Week 12. Conclusions. Treatment with omalizumab resulted in rapid clinical benefits in patients with CSU. Treatment with omalizumab was associated with reduction in FcɛRI+ and IgE+ basophils and intradermal cells

Retinoid-mediált jelátvitel szabályozása a bőrben és hatása a bőr homeosztázisra egérben

Endogenous retinoids like all-trans retinoic acid (ATRA) play important roles in skin physiology and immune-modulatory events in the skin via nuclear hormone receptor-mediated signaling through RARs and/or RXRs. Moreover, it has been shown recently that ATRA can activate another nuclear receptor involved in skin homeostasis, namely PPARδ, depending on specific transport proteins: Fabp5 initiates PPARδ signaling whereas Crabp2 promotes signaling via RAR. Notably, alterations in retinoid metabolism, signaling, and concentrations have been found in various skin diseases such as atopic dermatitis. Thereby, it remains unclear whether these changes are symptoms or the trigger of such diseases. The aim of this study was to determine how topically applied agonists or antagonists selective for RARs or RXRs and how the induction of an allergic immune response by systemic or combined systemic and topical treatment with ovalbumin influence retinoid metabolism and signaling in mouse skin. Of further interest were nuclear receptor ligand treatment effects on epidermal barrier homeostasis and skin-based immune regulation relevant for skin disorders such as atopic dermatitis, as well as their correlation to the allergen-induced dermatitis mouse model. Our data indicate that RARα and RARγ subtypes possess different roles in mouse skin and may be of relevance for the auto-regulation of endogenous retinoid signaling in the skin. Moreover, dysregulated retinoid signaling mediated by RXR, RARα and/or RARγ as well as potential unidentified pathways may promote skin-based inflammation and disturbance of epidermal barrier properties. This is further supported by elevated ATRA levels and mainly increased signaling mediated by RAR or PPARδ in allergen-induced dermatitis skin. Furthermore, systemic sensitization with an allergen is sufficient to modify the expression of genes central to epidermal homeostasis suggesting an “inside-out” effect of allergen in allergic skin disease pathogenesis possibly by increasing allergen penetration through the skin. In summary, disturbed retinoid metabolism and retinoid-mediated signaling in the skin may contribute to the development and/or maintenance of allergic skin diseases. Whether these alterations are symptoms or potential initiators of atopic sensitization still remains to be elucidated.d