Inflammation modulates intercellular adhesion and mechanotransduction in human epidermis via ROCK2
Authors
Maria S. Shutova, Julia Borowczyk, Barbara Russo, Sihem Sellami, Justyna Drukala, Michal Wolnicki, Nicolo C. Brembilla, Gurkan Kaya, Andrei I. Ivanov, Wolf-Henning Boehncke,
Institution
University and University Hospital of Geneva; Jagiellonian University, Cracow; Cleveland Clinic Foundation
Country
United States
Year
2023
Journal
iScience
Abstract
Aberrant mechanotransduction and compromised epithelial barrier function are associated with numerous human pathologies including inflammatory skin disorders. However, the cytoskeletal mechanisms regulating inflammatory responses in the epidermis are not well understood. Here we addressed this question by inducing a psoriatic phenotype in human keratinocytes and reconstructed human epidermis using a cytokine stimulation model. We show that the inflammation upregulates the Rho-myosin II pathway and destabilizes adherens junctions (AJs) promoting YAP nuclear entry. The integrity of cell-cell adhesion but not the myosin II contractilityper se is the determinative factor for the YAP regulation in epidermal keratinocytes. The inflammation-induced disruption of AJs, increased paracellular permeability, and YAP nuclear translocation are regulated by ROCK2, independently from myosin II activation. Using a specific inhibitor KD025, we show that ROCK2 executes its effects via cytoskeletal and transcription-dependent mechanisms to shape the inflammatory response in the epidermis.
Product use
Reconstructed human epidermis (RHE) model
Tissue type
Epidermal
Tissue info
N/TERT keratinocytes and primary juvenile keratinocytes