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 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...

Thymic stromal lymphopoietin is a critical mediator of IL‐13‐driven allergic inflammation

“…TNF-a or IL-1a), TLR ligands, and vitamin D in primary human bronchial epithelial cells and keratinocytes [16][17][18][19][20]. In such cell types, IL-13 alone did not induce TSLP production in contrast to the current results, although IL-13 was able to induce TSLP production in synergy with proinflammatory cytokines such as TNF-a [18][19][20].…”

Mast cell regulation of epithelial TSLP expression plays an important role in the development of allergic rhinitis

“…Previous studies suggest that TSLP expression in mouse keratinocytes is regulated by vitamin D and retinoic acid signaling [10] [17]. In addition, mast cells up-regulate the production of a variety of cytokines/chemokines in epithelial cells and fibroblasts, and induce the recruitment of basophils, T cells, and eosinophils into sites of allergic inflammation as well as their own intraepithelial accumulation.…”

“…Previous studies suggest that TSLP expression in mouse keratinocytes is regulated by vitamin D and retinoic acid signaling [10]. Most recently, TNF-a, IL-1b, and ligands for Toll-like receptors such as LPS were shown to up-regulate TSLP expression via NF-jB pathway in cultured human bronchial epithelial cells and keratinocytes [11][12][13].…”

NOD2 and TLR2 ligands trigger the activation of basophils and eosinophils by interacting with dermal fibroblasts in atopic dermatitis-like skin inflammation

“…[24][25][26] As shown in Figure 1a and e-h and the left-most panel of Figure 1d, topical administration of MC903 on the ears for 14 days induced tissue swelling, epidermal thickening, and the infiltration of eosinophils and basophils into the dermal layer. Strikingly, topical application of the NOD2/TLR2 ligands together with the AD-inducing agent MC903 further deteriorated the AD-like symptoms, including enhanced ear swelling (Figure 1a-c), more extensive epidermal thickening (Figure 1d and e), and the presence of a larger number of eosinophils in the dermal layer ( Figure 1g).…”

“…[24][25][26] A total of 2 nmol of MC903 (Sigma-Aldrich Corp, St. Louis, MO, USA), which is a Th2-related AD-like skin inflammation-inducing compound, was topically applied in 5 mL of ethanol to the ears of the mice every other day for 14 days (days 0-14, eight times in total). [24][25][26] Ear thickness was measured using a dial thickness gauge (Model G, Peacock, OZAKI MFG. CO., LTD, Tokyo, Japan) and recorded every other day for 16 days.…”