Inflammation modulates intercellular adhesion and mechanotransduction in human epidermis via ROCK2.
Inflammation modulates intercellular adhesion and mechanotransduction in human epidermis via ROCK2.
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炎症通过ROCK2调节人表皮细胞间黏附和机械转导。
DOI：
10.1016/j.isci.2023.106195
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发表时间：
2023-03-17
期刊：
影响因子：
5.8
通讯作者：
Boehncke, Wolf-Henning
中科院分区：
文献类型：
--
作者：
Shutova, Maria S.;Borowczyk, Julia;Russo, Barbara;Sellami, Sihem;Drukala, Justyna;Wolnicki, Michal;Brembilla, Nicolo C.;Kaya, Gurkan;Ivanov, Andrei I.;Boehncke, Wolf-Henning
异常的机械传导和受损的上皮屏障功能与许多人类病理学相关，包括炎症性皮肤病。然而，调节表皮炎症反应的细胞骨架机制尚不清楚。在这里，我们通过在人角质形成细胞中诱导银屑病表型并使用细胞因子刺激模型重建人表皮来解决这个问题。我们发现炎症上调 Rho-肌球蛋白 II 通路并破坏粘附连接 (AJ) 的稳定性，从而促进 YAP 进入核。细胞间粘附的完整性而非肌球蛋白 II 收缩性本身是表皮角质形成细胞中 YAP 调节的决定因素。炎症诱导的 AJ 破坏、细胞旁通透性增加和 YAP 核易位均受 ROCK2 调节，独立于肌球蛋白 II 激活。使用特定的抑制剂 KD025，我们证明 ROCK2 通过细胞骨架和转录依赖性机制发挥作用，塑造表皮的炎症反应。炎症破坏粘附连接并增强表皮中的机械信号传导 这些作用依赖于 Rho-ROCK2 通路，但不依赖肌球蛋白 ROCK2 抑制剂 KD025 部分挽救角质形成细胞炎症表型免疫学；免疫反应；基因组学
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. Inflammation disrupts adherens junctions and enhances mechanosignaling in the epidermis These effects rely on the Rho-ROCK2 pathway but are myosin independent ROCK2 inhibitor KD025 partially rescues the keratinocyte inflammatory phenotype Biological sciences; Immunology; Immune response; Genomics
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影响因子：
14.2
作者：
De Benedetto, Anna;Rafaels, Nicholas M;McGirt, Laura Y;Ivanov, Andrei I;Georas, Steve N;Cheadle, Chris;Berger, Alan E;Zhang, Kunzhong;Vidyasagar, Sadasivan;Yoshida, Takeshi;Boguniewicz, Mark;Hata, Tissa;Schneider, Lynda C;Hanifin, Jon M;Gallo, Richard L;Novak, Natalija;Weidinger, Stephan;Beaty, Terri H;Leung, Donald Y M;Barnes, Kathleen C;Beck, Lisa A
通讯作者：
Beck, Lisa A
影响因子：
6.5
作者：
Chung, E;Cook, PW;Coffey, RJ
通讯作者：
Coffey, RJ
DOI：
10.1159/000441541
发表时间：
2016-01-01
期刊：
SKIN BARRIER FUNCTION
影响因子：
--
作者：
Brandner, Johanna M.
通讯作者：
Brandner, Johanna M.
影响因子：
3.1
作者：
Naydenov NG;Baranwal S;Khan S;Feygin A;Gupta P;Ivanov AI
通讯作者：
Ivanov AI
影响因子：
6.5
作者：
Borowczyk, Julia;Buerger, Claudia;Brembilla, Nicolo Costantino
通讯作者：
Brembilla, Nicolo Costantino