Atopic dermatitis studies through in vitro models

Atopic dermatitis (AD) is a complex inflammatory skin condition that is not fully understood. Epidermal barrier defects and Th2 immune response dysregulations are thought to play crucial roles in the pathogenesis of the disease. A vicious circle takes place between these alterations, and it can further be complicated by additional genetic and environmental factors. Studies investigating in more depth the etiology of the disease are thus needed in order to develop functional treatments. In recent years, there have been significant advances regarding in vitro models reproducing important features of AD. However, since a lot of models have been developed, finding the appropriate experimental setting can be difficult. Therefore, herein, we review the different types of in vitro models mimicking features of AD. The simplest models are two-dimensional culture systems composed of immune cells or keratinocytes, whereas three-dimensional skin or epidermal equivalents reconstitute more complex stratified tissues exhibiting barrier properties. In those models, hallmarks of AD are obtained, either by challenging tissues with interleukin cocktails overexpressed in AD epidermis or by silencing expression of pivotal genes encoding epidermal barrier proteins. Tissue equivalents cocultured with lymphocytes or containing AD patient cells are also described. Furthermore, each model is placed in its study context with a brief summary of the main results obtained. In conclusion, the described in vitro models are useful tools to better understand AD pathogenesis, but also to screen new compounds in the field of AD, which probably will open the way to new preventive or therapeutic strategies

MβCD concurs with IL-4, IL-13 and IL-25 to induce alterations reminiscent of atopic dermatitis in reconstructed epidermis

Reconstructed human epidermis (RHE) mimic normal human in vivo epidermis in terms of histology, distribution of differentiation markers and barrier functionality. A typical transcriptional profile and the activation of signalling pathways reminiscent of atopic dermatitis (AD) lesional skin can be obtained in RHE upon incubation with methyl-β-cyclodextrin (MβCD), a molecule that extracts cholesterol from plasma membranes, thereby disrupting lipid microdomains. However, barrier function and morphology remain unaltered in those conditions, requiring further refinement of the model

ON LINNIK’S CONJECTURE: SUMS OF SQUARES AND MICROSQUARES

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Methyl-β-cyclodextrin concurs with interleukin (IL)-4, IL-13 and IL-25 to induce altercations reminiscent of atopic dermatitis in reconstructed human epidermis

Reconstructed human epidermis (RHE) mimic normal human in vivo epidermis in terms of histology, distribution of differentiation markers, and barrier functionality (1). A typical transcriptional profile and the activation of signalling pathways reminiscent of atopic dermatitis (AD) lesional skin can be obtained in RHE upon incubation with methyl-β-cyclodextrin (MβCD) (2, 3), a molecule that extracts cholesterol from plasma membranes, thereby disrupting lipid microdomains. However, barrier function and morphology remain unaltered in those conditions, requiring further refinement of the model

Keratinocytes activated by IL-4/IL-13 express IL-2Rgamma with consequences on epidermal barrier function.

Atopic dermatitis (AD) is a Th2-type inflammatory disease characterized by an altera- tion of epidermal barrier following the release of IL-4 and IL-13. These cytokines ac- tivate type II IL-4Rα/IL-13Rα1 receptors in the keratinocyte. Whilst IL-2Rγ, that forms type I receptor for IL-4, is only expressed in haematopoietic cells, recent studies sug- gest its induction in keratinocytes, which questions about its role. We studied expres- sion of IL-2Rγ in keratinocytes and its role in alteration of keratinocyte function and epidermal barrier. IL-2Rγ expression in keratinocytes was studied using both recon- structed human epidermis (RHE) exposed to IL-4/IL-13 and AD skin. IL-2Rγ induction by type II receptor has been analyzed using JAK inhibitors and RHE knockout (KO) for IL13RA1. IL-2Rγ function was investigated in RHE KO for IL2RG. In RHE, IL-4/IL-13 in- duce expression of IL-2Rγ at the mRNA and protein levels. Its mRNA expression is also visualized in keratinocytes of lesional AD skin. IL-2Rγ expression is low in RHE treated with JAK inhibitors and absent in RHE KO for IL13RA1. Exposure to IL-4/IL-13 alters epidermal barrier, but this alteration is absent in RHE KO for IL2RG. A more important induction of IL-13Rα2 is reported in RHE KO for IL2RG than in not edited RHE. These results demonstrate IL-2Rγ induction in keratinocytes through activation of type II receptor. IL-2Rγ is involved in the alteration of the epidermal barrier and in the regula- tion of IL-13Rα2 expression. Observation of IL-2Rγ expression by keratinocytes inside AD lesional skin suggests a role for this receptor subunit in the disease