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

TY - JOUR

T1 - Tight Junction Proteins Claudin-1 and Occludin Are Important for Cutaneous Wound Healing

AU - Volksdorf, Thomas

AU - Heilmann , Janina

AU - Eming, Sabine A

AU - Schawjinski , Kathrin

AU - Zorn-Kruppa, Michaela

AU - Ueck, Christopher

AU - Vidal-Y-Sy, Sabine

AU - Windhorst, Sabine

AU - Jücker, Manfred

AU - Moll, Ingrid

AU - Brandner, Johanna M

N1 - Copyright © 2017. Published by Elsevier Inc.

PY - 2017/6

Y1 - 2017/6

N2 - 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.

AB - 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.

KW - Journal Article

U2 - 10.1016/j.ajpath.2017.02.006

DO - 10.1016/j.ajpath.2017.02.006

M3 - SCORING: Journal article

C2 - 28412298

VL - 187

SP - 1301

EP - 1312

JO - AM J PATHOL

JF - AM J PATHOL

SN - 0002-9440

IS - 6

ER -