Abstract
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 (ΔNp63lo/-). 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 ΔNp63lo/- 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.
Highlights
The prevalence of allergic disorders has been significantly increasing in many countries in the past few decades
To the best of our knowledge, this study is the first study showing that thymic stromal lymphopoietin (TSLP) receptors are physiologically presented by superficial keratinocytes of normal skin tissues and their expression is associated with DNp63
We demonstrated that the epidermal lesions of atopic dermatitis (AD) preferentially contain a large amount of DNp63lo/- keratinocytes
Summary
The prevalence of allergic disorders has been significantly increasing in many countries in the past few decades. Children suffering from AD will frequently be affected by other allergic disorders such as allergic asthma or rhinitis, following a process known as the ‘atopic march’ [2,3]. Since the mechanism of AD has not been fully elucidated, an understanding of the process underlying AD should help to formulate appropriate therapies for improvement in quality of life and for prevention of ADrelated allergic disorders. Recent genome-wide association studies on AD patients have revealed somatic mutations of genes regulating keratinocytes such as those for filaggrin, a natural skin moisturizer, and claudin-1, a representative barrier protein [7,8,9]. Functional loss of filaggrin disrupts the epidermal skin barrier and causes keratinocytes to produce TSLP [10]. The dysfunction of filaggrin is not sufficient to explain the mechanism underlying TSLP overproduction by keratinocytes
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