Inflammation modulates intercellular adhesion and mechanotransduction in human epidermis via ROCK2
Maria S. Shutova,
Julia Borowczyk,
Barbara Russo,
Sihem Sellami,
Justyna Drukala,
Michal Wolnicki,
Nicolo C. Brembilla,
Gurkan Kaya,
Andrei I. Ivanov,
Wolf-Henning Boehncke
Affiliations
Maria S. Shutova
University of Geneva, Department of Pathology and Immunology, Geneva, Switzerland; University Hospitals of Geneva, Division of Dermatology and Venereology, Geneva, Switzerland; Geneva Centre for Inflammation Research, Faculty of Medicine, University of Geneva, Geneva, Switzerland; Corresponding author
Julia Borowczyk
University of Geneva, Department of Pathology and Immunology, Geneva, Switzerland
Barbara Russo
University of Geneva, Department of Pathology and Immunology, Geneva, Switzerland; University Hospitals of Geneva, Division of Dermatology and Venereology, Geneva, Switzerland; Geneva Centre for Inflammation Research, Faculty of Medicine, University of Geneva, Geneva, Switzerland
Sihem Sellami
University of Geneva, Department of Pathology and Immunology, Geneva, Switzerland
Justyna Drukala
Jagiellonian University, Department of Cell Biology, Faculty of Biochemistry, Biophysics and Biotechnology, Cracow, Poland
Michal Wolnicki
Department of Pediatric Urology, Jagiellonian University Medical College, Cracow, Poland
Nicolo C. Brembilla
University Hospitals of Geneva, Division of Dermatology and Venereology, Geneva, Switzerland; Geneva Centre for Inflammation Research, Faculty of Medicine, University of Geneva, Geneva, Switzerland
Gurkan Kaya
University Hospitals of Geneva, Division of Dermatology and Venereology, Geneva, Switzerland
Andrei I. Ivanov
Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH, USA
Wolf-Henning Boehncke
University of Geneva, Department of Pathology and Immunology, Geneva, Switzerland; University Hospitals of Geneva, Division of Dermatology and Venereology, Geneva, Switzerland; Geneva Centre for Inflammation Research, Faculty of Medicine, University of Geneva, Geneva, Switzerland; Corresponding author
Summary: 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 contractility per 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.
