TSLP is a direct trigger for T cell migration in filaggrin-deficient skin equivalents

Leonie Wallmeyer,Burkhard Kleuser,Michaela Sochorová,Kateřina Vávrová,Kristina Dietert,Achim D Gruber,Sarah Hedtrich

doi:10.1038/s41598-017-00670-2

Leonie Wallmeyer, Burkhard Kleuser + Show 5 more

Open Access

https://doi.org/10.1038/s41598-017-00670-2

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Abstract

Mutations in the gene encoding for filaggrin (FLG) are major predisposing factors for atopic dermatitis (AD). Besides genetic predisposition, immunological dysregulations considerably contribute to its pathophysiology. For example, thymic stromal lymphopoietin (TSLP) is highly expressed in lesional atopic skin and significantly contributes to the pathogenesis of AD by activating dendritic cells that then initiate downstream effects on, for example, T cells. However, little is known about the direct interplay between TSLP, filaggrin-deficient skin and other immune cells such as T lymphocytes. In the present study, FLG knockdown skin equivalents, characterised by intrinsically high TSLP levels, were exposed to activated CD4+ T cells. T cell exposure resulted in an inflammatory phenotype of the skin equivalents. Furthermore, a distinct shift from a Th1/Th17 to a Th2/Th22 profile was observed following exposure of T cells to filaggrin-deficient skin equivalents. Interestingly, TSLP directly stimulated T cell migration exclusively in filaggrin-deficient skin equivalents even in the absence of dendritic cells, indicating a hitherto unknown role of TSLP in the pathogenesis of AD.

Highlights

Atopic dermatitis (AD), a chronic inflammatory skin disease, has a major detrimental impact on patient quality of life[1]
Exposure to non-activated T cells did not increase IL-6 or IL-8 release, (Supplementary Fig. S3) and levels of IL-25 (IL-17E) and IL-33 were below detection limit
The crosstalk between immune and skin cells play a central role in the pathophysiology of atopic dermatitis (AD) and other inflammatory skin disorders[29, 30]

Summary

Introduction

Atopic dermatitis (AD), a chronic inflammatory skin disease, has a major detrimental impact on patient quality of life[1]. The importance of TSLP in the pathogenesis of allergic diseases is widely recognised, little is currently known about the direct interplay between TSLP, filaggrin-deficient skin and naïve CD4+ T cells in humans. The regulation of cornified envelope and tight junction proteins, skin surface pH, pro-inflammatory cytokine secretion, skin lipid composition and barrier function of the skin equivalents in the presence of the T cells were assessed. Using this in vitro model, previously unidentified down-stream effects between filaggrin-deficient skin, TSLP expression, and T cell migration were identified

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