Abstract
Atopic dermatitis (AD) is characterized by dry and itchy skin evolving into disseminated skin lesions. AD is believed to result from a primary acquired or a genetically-induced epidermal barrier defect leading to immune hyper-responsiveness. Filaggrin (FLG) is a protein found in the cornified envelope of fully differentiated keratinocytes, referred to as corneocytes. Although FLG null mutations are strongly associated with AD, they are not sufficient to induce the disease. Moreover, most patients with ichthyosis vulgaris (IV), a monogenetic skin disease characterized by FLG homozygous, heterozygous, or compound heterozygous null mutations, display non-inflamed dry and scaly skin. Thus, all causes of epidermal barrier impairment in AD have not yet been identified, including those leading to the Th2-predominant inflammation observed in AD. Three dimensional organotypic cultures have emerged as valuable tools in skin research, replacing animal experimentation in many cases and precluding the need for repeated patient biopsies. Here, we review the results on IV and AD obtained with epidermal or skin equivalents and consider these findings in the context of human in vivo data. Further research utilizing complex models including immune cells and cutaneous innervation will enable finer dissection of the pathogenesis of AD and deepen our knowledge of epidermal biology.
Highlights
Atopic dermatitis (AD) is one of the most common inflammatory skin diseases worldwide
We have shown that human epidermis (HEEs) generated with KCs isolated from ichthyosis vulgaris (IV) patients (Figure 1) recapitulated the abnormalities observed in the epidermis of IV patients, i.e., disorganized lamellar bilayer structures
Our work has shown that both proteins were strongly reduced in IV HEEs, where no Th2 cytokine was added, suggesting that another mechanism is involved [49]
Summary
Atopic dermatitis (AD) is one of the most common inflammatory skin diseases worldwide. This latter phenotype results from disruption of the mature lamellar bilayer organization, owing to incompletely processed lamellar material, aberrant LB internal structures and LB entombment, premature secretion of LB contents into the extracellular spaces of the SG, and inhomogeneous secretion at the SG-SC interface [19,49] Overall, these studies show that subtle changes in epidermal lipid composition observed in FLG deficiency are sufficient to disorganize SC lipids and alter LB formation, albeit other factors such as the F-actin cytoskeleton might be involved [53]. Van Drongelen et al generated HEEs with immortalized (N/TERT) KCs knocked down for FLG and observed normal epidermal and SC thickness and SC lamellar lipid organization, consistent with a lack of permeability to butyl para-aminobenzoic acid (butyl-PABA), a lipophilic compound, and thereby demonstrating no alteration of the SC barrier in their model [52]. In the future, both the humidity and temperature of 3D cultures should be more carefully considered, especially for studying epidermal barrier function
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