LAUSR

The skin is one of the largest organs in the human body, and its main function is maintenance and regulation of the interface between body and external environment. The epidermis in particular plays a critical role in providing a barrier to water loss. Keratinocytes, specialized epithelial cells in the epidermis, undergo a complex and highly regulated process of terminal differentiation to form two main barrier structures: the stratum corneum (SC), the outmost layer, and tight junctions (TJs), in the stratum granulosum. For a long time, TJs in the epidermis have been overlooked, with most studies focusing on the role of the SC as the major component of the skin barrier. Over the past two decades, there have been substantial advances in our understanding of TJ function and composition in the epidermis, as well as in our knowledge of TJ involvement in several inflammatory skin conditions. TJs seal the intercellular spaces between epithelial cells, and the ‘tightness’ of this structure is dynamically regulated. A critical function attributed to TJs in the epidermis is to provide a dynamic barrier to water, macromolecules and ions. A seminal paper by Furuse et al. published in 2002, showing extreme (lethal) transepidermal water loss in claudin-1 knockout mice, was the first strong evidence of the role played by TJs (and claudin-1) in the epidermal water barrier. Despite a growing body of research in this field, the mechanism(s) that regulate water loss in the epidermis and the role of TJs remain poorly understood. In this issue of the BJD, El-Chami et al. present an original work investigating the expression of osmolyte transporters in keratinocytes, and the effects of osmolytes on the function and composition of epidermal TJs. While a large body of evidence is available to support the role of organic osmolytes and their transporters in water homeostasis in several organs (e.g. kidney), studies in skin are still limited (reviewed in El-Chami et al.). Stimulation of skin explants with organic osmolytes induced upregulation of specific transporters, and this was associated with an increase in expression of key TJ components. To perform functional assays the authors employed a submerged keratinocyte model, with confluent keratinocytes cultured in high-calcium media to induce differentiation. Under these conditions, stimulation with betaine, taurine and myo-inositol enhanced TJ integrity, as shown by enhanced transepithelial electrical resistance (i.e. barrier to ions) and reduced permeability (i.e. barrier to macromolecules). Functional changes were associated with enhanced expression of claudin-1 and -4. Notably, use of transporter inhibitors blocked the effect. In summary, the manuscript unveils a novel pathway of TJ regulation by organic osmolytes and a possible role in water barrier regulation. Also, the study suggests a mechanism by which TJs dynamically respond to changes in skin osmolarity/hydration, which is interesting because of its implication for the maintenance of ionic gradients in the epidermis. Findings from this study are important as they provide insights into the function and mechanism of organic osmolytes (betaine and taurine) as a skin barrier enhancer. This has a direct translational application, as organic osmolytes such as betaine and taurine are often used in skincare products. There is an unmet need to better understand epidermal barrier regulation, not only as it applies to general skincare but also to treatment of common skin conditions, from atopic dermatitis to xerosis. One limitation of this study, as of others in this field, is the lack of a validated and universally accepted in vitro (and in vivo) model to study epidermal TJs. Submerged keratinocyte culture systems are a convenient, low-cost and quick platform to investigate assembly and composition of TJs in primary keratinocytes. However, such systems do not allow for terminal differentiation of keratinocytes or full stratification, and do not take into account the complex interactions between TJ and SC components. Nevertheless, they provide a good model for initial investigation that must be validated in more complex systems and in vivo. The challenge for the field is to establish a model, or potentially more than one depending on the outcomes, that truly reassembles the complexity of TJs in the epidermis, while still being accessible and affordable. There is still much to be unveiled about the function and regulation of TJs in the epidermis, and with the right tools and relevant research questions, this field is poised to bring important change in the understanding of skin barrier pathophysiology.