Division of Pulmonary, Critical Care and Sleep Medicine, Department of Internal Medicine, University of Kansas Medical Center, Kansas City, KS, U.S.A.
Clin Sci (Lond). 2024 Oct 2;138(19):1209-1226. doi: 10.1042/CS20240064.
Allergens and Th2 cytokines affect the homeostatic environment in the airways, leading to increased mucus production by goblet cells associated with altered adherens junctional complex (AJC) and tight junction (TJ) proteins responsible for maintaining epithelial barrier function. Circadian clock-dependent regulatory mechanisms such as inflammation and epithelial barrier function are gaining more attention due to their therapeutic potential against allergic inflammatory lung diseases. Currently, there are no studies to support whether REV-ERBα activation can attenuate Th2 cytokine-induced epithelial barrier dysfunction in human bronchial epithelial cells. We hypothesized that Th2 cytokine-induced epithelial barrier dysfunction may be protected by activating REV-ERBα. Treatment with Th2 cytokines or HDM significantly reduced the cell impedance, as confirmed by transepithelial electrical resistance (TEER). However, pre-treatment with SR10067 attenuated Th2 cytokine-induced barrier dysfunction, such as decreased permeability, improved TEER, localization of AJC and TJ proteins, and mRNA and protein levels of selected epithelial barrier and circadian clock targets. Overall, we showed for the first time that REV-ERBα activation regulates altered epithelial barrier function that may have direct implications for the treatment of asthma and other allergic diseases.
过敏原和 Th2 细胞因子会影响气道中的内稳态环境，导致与黏附连接复合体 (AJC) 和紧密连接 (TJ) 蛋白改变相关的杯状细胞产生更多黏液，而这些蛋白负责维持上皮屏障功能。由于昼夜节律依赖性调节机制（如炎症和上皮屏障功能）具有治疗过敏性炎症性肺病的潜力，因此越来越受到关注。目前尚无研究支持 REV-ERBα 激活是否可以减轻 Th2 细胞因子诱导的人支气管上皮细胞上皮屏障功能障碍。我们假设 Th2 细胞因子诱导的上皮屏障功能障碍可以通过激活 REV-ERBα 来保护。Th2 细胞因子或 HDM 的处理显著降低了细胞阻抗，这通过跨上皮电阻 (TEER) 得到证实。然而，SR10067 的预处理减轻了 Th2 细胞因子诱导的屏障功能障碍，例如降低通透性、提高 TEER、AJC 和 TJ 蛋白的定位以及选定的上皮屏障和昼夜节律靶点的 mRNA 和蛋白水平。总的来说，我们首次表明，REV-ERBα 的激活调节改变的上皮屏障功能，这可能对哮喘和其他过敏性疾病的治疗具有直接意义。
