We have demonstrated that cytokine thymic stromal lymphopoietin (TSLP), whose expression is rapidly induced upon keratinocyteselective ablation of retinoid X receptors (RXRs) -␣ and - in the mouse (RXR␣ 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 [1␣,25-(OH) 2D3; 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 RXR␣ ep؊/؊ mutants and transgenic mice overexpressing TSLP in keratinocytes. Furthermore, topical application of retinoic acid receptor RAR␥-selective agonist BMS961 also induces TSLP expression either on its own or synergistically with 1␣,25-(OH)2D3. Our data demonstrate that RXR͞ vitamin D receptor and RXR͞retinoic acid receptor-␥ 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.retinoic acid ͉ vitamin D receptor ͉ retinoid X receptor ͉ retinoic acid receptor ͉ skin N uclear receptors (NRs) belong to a superfamily of liganddependent transcriptional regulators (1, 2). Within this superfamily, retinoid X receptors (RXRs) -␣, -, and -␥ play a key role through heterodimerization with some 15 NR partners, e.g., retinoic acid receptors (RARs), vitamin D receptor (VDR), peroxisome proliferator-activated receptors, and liver X receptors (1, 2). We reported (3) that selective ablation of RXR␣ and RXR in adult mouse epidermal keratinocytes (RXR␣ epϪ/Ϫ mice) triggers a skin and systemic syndrome similar to human atopic dermatitis (AD), a chronic skin inflammatory disease with a strong genetic component that affects children (10-20%) and adults (1-3%) (4). These mice exhibit the major features of the human AD syndrome that include (i) skin eczematous-like lesions with xerosis and pruritus, associated with a skin inflammatory infiltrate mainly composed of CD4 ϩ T helper (Th) type 2 cells, dendritic cells, eosinophils, and mast cells and (ii) systemic abnormalities, including elevated serum IgE and IgG levels and blood and tissue eosinophilia.We found that expression of the cytokine thymic stromal lymphopoietin (TSLP), known to be produced in epidermal keratinocytes of AD patients (5), is rapidly induced in keratinocytes of RXR␣ epϪ/Ϫ mice. Furthermore, we showed that K14-TSLP transgenic mice overexpressing TSLP in keratinocytes exhibit an ADlike phenotype similar to that of RXR␣ epϪ/Ϫ mice (3), demonstrating that TSLP can act as an initiating cytokine at the top of a chain of immunological events that lead to an AD-like phenotype, in keeping with other recent studies on mouse models of human allergic inflammatory diseases (asthma and AD) (6-9).We suggested that up-regulation of keratinocytic TSLP...
Atopic dermatitis often precedes the development of asthma, a phenomenon known as "atopic march". An important role of allergen sensitization developed through barrier-defective skin has been recognized in the onset of atopic march; however, the underlying mechanism remains poorly understood. In this study, we use an experimental atopic march mouse model, in which the sensitization to allergen is achieved through barrier-impaired skin, followed by allergen challenge in the airway. By using thymic stromal lymphopoietin (TSLP)(iep-/-) mice in which the cytokine TSLP is selectively and inducibly ablated in epidermal keratinocytes, we demonstrate that keratinocytic TSLP, the expression of which is induced by skin barrier impairment, is essential for generating skin allergic inflammation and allergen-induced T helper type 2 response, for developing sensitization to allergen, and for triggering a subsequent allergic asthma. Furthermore, using TSLP(over) mice in which overexpression of keratinocytic TSLP is induced by skin topical application of MC903 (a vitamin D3 analog) in a dose-dependent manner, we show that keratinocytic TSLP levels are correlated with skin sensitization strength and asthma severity. Taken together, our study uncovers a crucial role of keratinocytic TSLP in the "atopic march" by promoting allergen sensitization occurring in barrier-impaired skin, which ultimately leads to allergic asthma.
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.A topic dermatitis (AD) is a common skin disease that is often associated with other atopic disorders, such as asthma and allergic rhinitis. AD, characterized by pruritic and eczematoid skin lesions, affects children (10%-20%) and adults (1%-3%) (1, 2). Asthma is a chronic airway inflammatory disease, exhibiting lung allergic inflammation, mucus hypersecretion, and airway hyperreactivity (AHR) (3, 4). Epidemiologic analysis shows that AD is often the initial step in the so-called ''atopic march'' (1, 5-7), given that more than 50% of AD patients with moderate to severe AD develop asthma later in life, and the severity of AD influences the course of respiratory allergy. Both AD and asthma share an ''atopy'' phenotype that includes a T helper type 2 (Th2) inflammation with eosinophilia and hyper-IgE immunoglobulinemia (5, 6), but the molecular mechanisms underlying the ''atopic march'' remain unclear.Recently, thymic stromal lymphopoietin (TSLP) emerged as a likely master regulator of AD inflammation (8-10). Overproduction of TSLP was found in keratinocytes of human AD skin lesions (11). We reported that selective ablation of retinoid X receptors (RXRs) in epidermal keratinocytes in adult mice induces TSLP expression in epidermis and triggers an AD-like syndrome (12). Our study (12) and a study by Yoo et al. (13) demonstrated that mice overexpressing TSLP in keratinocytes developed a similar AD-like dermatitis. More recently, we showed that topical application of MC903 (calcipotriol; a low-calcemic analogue of vitamin D3) (14) triggers an AD-like syndrome through the induction of keratinocytic TSLP expression (15,16). On the basis of these results, which indicate that TSLP is both sufficient and necessary in triggering an AD inflammation, and the fact that asthma is often associated with AD, we speculated that the occurrence of asthma may be increased in mice exhibiting TSLP-induced AD.To investigate this possibility, mice topically treated with MC903 (16) were subjected to an ovalbumin (OVA)-induced asthma protocol, in which OVA sensitization and intranasal challenge induce characteristic feat...
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