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

doi:10.1016/j.isci.2023.106195

Inflammation modulates intercellular adhesion and mechanotransduction in human epidermis via ROCK2

iScience. 2023 Feb 14;26(3):106195. doi: 10.1016/j.isci.2023.106195. eCollection 2023 Mar 17.

Authors

Maria S Shutova^{1

2

3}, Julia Borowczyk¹, Barbara Russo^{1

2

3}, Sihem Sellami¹, Justyna Drukala⁴, Michal Wolnicki⁵, Nicolo C Brembilla^{2

3}, Gurkan Kaya², Andrei I Ivanov⁶, Wolf-Henning Boehncke^{1

2

3}

Affiliations

¹ University of Geneva, Department of Pathology and Immunology, Geneva, Switzerland.
² University Hospitals of Geneva, Division of Dermatology and Venereology, Geneva, Switzerland.
³ Geneva Centre for Inflammation Research, Faculty of Medicine, University of Geneva, Geneva, Switzerland.
⁴ Jagiellonian University, Department of Cell Biology, Faculty of Biochemistry, Biophysics and Biotechnology, Cracow, Poland.
⁵ Department of Pediatric Urology, Jagiellonian University Medical College, Cracow, Poland.
⁶ Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH, USA.

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 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.

Keywords: Biological sciences; Genomics; Immune response; Immunology.

Grants and funding

R01 DK126702/DK/NIDDK NIH HHS/United States