Tight Junction Proteins Claudin-1 and Occludin Are Important for Cutaneous Wound Healing

Abstract

Tight junction (TJ) proteins are known to be involved in proliferation and differentiation. These processes are essential for normal skin wound healing. Here, we investigated the TJ proteins claudin-1 and occludin in ex vivo skin wound healing models and tissue samples of acute and chronic human wounds and observed major differences in localization/expression of these proteins, with chronic wounds often showing a loss of the proteins at the wound margins and/or in the regenerating epidermis. Knockdown experiments in primary human keratinocytes showed that decreased claudin-1 expression resulted in significantly impaired scratch wound healing, with delayed migration and reduced proliferation. Activation of AKT pathway was significantly attenuated after claudin-1 knockdown, and protein levels of extracellular signal-related kinase 1/2 were reduced. For occludin, down-regulation had no impact on wound healing in normal scratch assays, but after subjecting the cells to mechanical stress, which is normally present in wounds, wound healing was impaired. For both proteins we show that most of these actions are independent from the formation of barrier-forming TJ structures, thus demonstrating nonbarrier-related functions of TJ proteins in the skin. However, for claudin-1 effects on scratch wound healing were more pronounced when TJs could form. Together, our findings provide evidence for a role of claudin-1 and occludin in epidermal regeneration with potential clinical importance.

Differential Expression and Function of Bicellular Tight Junctions in Skin and Oral Wound Healing

“…A recent study by Volksdorf et al showed that loss of claudin 1 and occludin occurs at the wound margins of chronic wounds and in the regenerating epidermis [16]. On the basis of these results, together with our microarray analyses, we hypothesized that inhibition of CLDN1 or OCLN expression could affect the migratory and proliferative capacity of skin and oral keratinocytes.…”

“…TJs also maintain cell polarity and prevent mixing of molecules from the apical and lateral membranes, a role termed fence function. In addition, some TJ genes also regulate the proliferation and migration of epithelial cells [15,16] and are involved in the immune response [17]. Given the differential healing phenotypes of cutaneous skin and oral wounds and the critical roles that TJs play in various tissues, we hypothesized that the repertoire of expressed TJ genes may be different between the skin and oral cavity in both intact epithelial cells and in a wound healing setting.…”

3D skin models for 3R research: The potential of 3D reconstructed skin models to study skin barrier function

“…In addition, they influence SC formation and function . Furthermore, TJ proteins have been shown to be involved in keratinocyte proliferation, differentiation, migration, apoptosis and cell‐cell adhesion . Thus, TJs and distinct TJ proteins are interesting to address for investigation of epidermal barrier function, epidermal differentiation, epidermal ion gradients and wound healing.…”

Antiwrinkle and antimelanogenesis activity of the ethanol extracts of Lespedeza cuneata G. Don for development of the cosmeceutical ingredients

“…Thus, we analyzed the expression level of Claudin1, Occludin, and ZO‐1 in HaCaT human keratinocytes treated with the ethanol extract of L. cuneata G. Don by Western blotting. As shown in Figure a, Claudin1, Occludin, and ZO‐1 was up‐regulated by the ethanol extract of L. cuneata G. Don in HaCaT cells, which was confirmed by wound healing migration assay as the enhanced TJ function can affect cell mobility and migration (Volksdorf et al., ) (Figure b). The treatment of 250 and 500 μg/ml of the ethanol extract of L. cuneata G. Don has significantly increased the expression of Claudin1, Occludin, and ZO‐1 compared to the vehicle control.…”

“…Among these proteins, claudins have several types of isomers that are mainly responsible for TJ depending on the tissue types (Shigetomi & Ikenouchi, 2017). Especially, in skin keratinocytes, claudin-1 is known to be involved in regulation of TJ and its functional mechanism has been studied by several recent reports (Tokumasu, Tamura, & Tsukita, 2017;Tokumasu et al, 2016;Volksdorf et al, 2017). As TJ plays a significant role in skin barrier function, researcher have been considering the novel way for preventing and strengthening skin barrier by the development of various cosmetic materials to control TJ in skin.…”