Shutova Maria S, Borowczyk Julia, Russo Barbara, Sellami Sihem, Drukala Justyna, Wolnicki Michal, Brembilla Nicolo C, Kaya Gurkan, Ivanov Andrei I, Boehncke Wolf-Henning
University of Geneva, Department of Pathology and Immunology, Geneva, Switzerland.
University Hospitals of Geneva, Division of Dermatology and Venereology, Geneva, Switzerland.
iScience. 2023 Feb 14;26(3):106195. doi: 10.1016/j.isci.2023.106195. eCollection 2023 Mar 17.
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 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.
异常的机械转导和受损的上皮屏障功能与包括炎症性皮肤病在内的多种人类疾病相关。然而，调节表皮炎症反应的细胞骨架机制尚未完全明确。在此，我们通过细胞因子刺激模型在人角质形成细胞和重建的人表皮中诱导银屑病表型来解决这个问题。我们发现，炎症上调Rho-肌球蛋白II通路并破坏黏附连接（AJs）的稳定性，促进YAP进入细胞核。细胞间黏附的完整性而非肌球蛋白II的收缩性是表皮角质形成细胞中YAP调节的决定性因素。炎症诱导的AJs破坏、细胞旁通透性增加和YAP核转位由ROCK2调节，与肌球蛋白II激活无关。使用特异性抑制剂KD025，我们发现ROCK2通过细胞骨架和转录依赖性机制发挥作用，以塑造表皮中的炎症反应。
