REV-ERBα agonist SR10067 attenuates Th2 cytokine-mediated barrier dysfunction in human bronchial epithelial cells.

IF 6.7 2区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Clinical science Pub Date : 2024-10-02 DOI:10.1042/CS20240064
Santhosh Kumar Duraisamy, Isaac Kirubakaran Sundar
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Abstract

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.

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REV-ERBα激动剂 SR10067 可减轻 Th2 细胞因子介导的人支气管上皮细胞屏障功能障碍。
过敏原和 Th2 细胞因子会影响气道内的平衡环境,导致鹅口疮细胞分泌更多粘液,并导致负责维持上皮屏障功能的粘连连接复合体(AJC)和紧密连接(TJ)蛋白发生改变。昼夜节律钟依赖性调控机制(如炎症和上皮屏障功能)因其对过敏性炎症性肺病的治疗潜力而日益受到关注。目前,还没有研究证实 REV-ERBα 激活能否减轻 Th2 细胞因子诱导的人类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通过激活 REV-ERBα 得到保护。经上皮电阻(TEER)证实,Th2 细胞因子或 HDM 可显著降低细胞阻抗。然而,SR10067 的预处理减轻了 Th2 细胞因子诱导的屏障功能障碍,如通透性降低、TEER 改善、AJC 和 TJ 蛋白定位以及选定的上皮屏障和昼夜节律钟靶标的 mRNA 和蛋白水平。总之,我们首次发现了 REV-ERBα 激活调控上皮屏障功能的改变,这可能对治疗哮喘和其他过敏性疾病有直接影响。
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来源期刊
Clinical science
Clinical science 医学-医学:研究与实验
CiteScore
11.40
自引率
0.00%
发文量
189
审稿时长
4-8 weeks
期刊介绍: Translating molecular bioscience and experimental research into medical insights, Clinical Science offers multi-disciplinary coverage and clinical perspectives to advance human health. Its international Editorial Board is charged with selecting peer-reviewed original papers of the highest scientific merit covering the broad spectrum of biomedical specialities including, although not exclusively: Cardiovascular system Cerebrovascular system Gastrointestinal tract and liver Genomic medicine Infection and immunity Inflammation Oncology Metabolism Endocrinology and nutrition Nephrology Circulation Respiratory system Vascular biology Molecular pathology.
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