<br>唾液腺上皮细胞中 GPX4 下调通过脂质 ROS/pSTAT4/AQP5 轴导致干燥综合征唾液分泌功能障碍,Free Radical Biology and Medicine

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唾液腺上皮细胞中 GPX4 下调通过脂质 ROS/pSTAT4/AQP5 轴导致干燥综合征唾液分泌功能障碍
Free Radical Biology and Medicine ( IF 7.1 ) Pub Date : 2024-04-02 , DOI: 10.1016/j.freeradbiomed.2024.04.003
Jiannan Zhou ₁ , Janak L Pathak ₁ , Lihong Wu ₁ , Bo Chen ₁ , Tingting Cao ₁ , Wei Wei ₂ , Xiaodan Wu ₁ , Guiping Chen ₁ , Nobumoto Watanabe ₃ , Xiaomeng Li ₄ , Jiang Li ₁

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干燥综合征（SS）是一种自身免疫性疾病，其特征是外分泌腺（例如唾液腺）功能障碍。然而，SS唾液分泌功能障碍的分子机制仍不清楚。鉴于谷胱甘肽过氧化物酶 4 (GPX4) 在细胞氧化还原稳态中的重要性，我们假设 GPX4 的失调可能在 SS 中观察到的唾液分泌功能障碍的发病机制中发挥关键作用。 SS患者和SS小鼠模型的唾液腺中铁死亡抑制剂GPX4和参与唾液分泌的重要蛋白水通道蛋白5（AQP5）的表达减少。 GPX4 过表达上调，GPX4 敲除下调唾液腺上皮细胞 (SGEC) 和唾液分泌中 AQP5 的表达。对 SS 患者唾液腺 GSE 数据库的生物信息学分析表明 STAT4 是 GPX4 和 AQP5 之间的关键中介调节因子。在 SS 小鼠模型的唾液腺中观察到较高水平的核 pSTAT4。 GPX4 过表达受到抑制，而 GPX4 敲低则促进 SGEC 中 STAT4 磷酸化和核转位。 CHIP 测定证实 pSTAT4 与 AQP5 启动子内的结合抑制 AQP5 转录。 GPX4 下调会在 SGEC 中积累细胞内脂质 ROS。脂质 ROS 抑制剂 Ferrostatin-1 处理在体外和体内研究中证实，脂质 ROS 激活 SGEC 中的 STAT4 磷酸化和核转位。总之，SGEC 中 GPX4 的下调通过脂质 ROS/pSTAT4/AQP5 轴导致 SS 唾液分泌功能障碍。这项研究揭示了恢复 SS 患者唾液分泌功能的新靶点。

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Downregulated GPX4 in salivary gland epithelial cells contributes to salivary secretion dysfunction in Sjogren's syndrome via lipid ROS/pSTAT4/AQP5 axis

Sjogren's syndrome (SS) is an autoimmune disease characterized by dysfunction of exocrine glands, such as salivary glands. However, the molecular mechanism of salivary secretion dysfunction in SS is still unclear. Given the significance of glutathione peroxidase 4 (GPX4) in cellular redox homeostasis, we hypothesized that dysregulation of GPX4 may play a pivotal role in the pathogenesis of salivary secretion dysfunction observed in SS. The salivary gland of SS patients and the SS mouse model exhibited reduced expression of the ferroptosis inhibitor GPX4 and the important protein aquaporin 5 (AQP5), which is involved in salivary secretion. GPX4 overexpression upregulated and GPX4 knockdown downregulated AQP5 expression in salivary gland epithelial cells (SGECs) and salivary secretion. Bioinformatics analysis of GSE databases from SS patients' salivary glands revealed STAT4 as a key intermediary regulator between GPX4 and AQP5. A higher level of nuclear pSTAT4 was observed in the salivary gland of the SS mouse model. GPX4 overexpression inhibited and GPX4 knockdown promoted STAT4 phosphorylation and nuclear translocation in SGECs. CHIP assay confirmed the binding of pSTAT4 within the promoter of AQP5 inhibiting AQP5 transcription. GPX4 downregulation accumulates intracellular lipid ROS in SGECs. Lipid ROS inhibitor ferrostatin-1 treatment during in vitro and in vivo studies confirmed that lipid ROS activates STAT4 phosphorylation and nuclear translocation in SGECs. In summary, the downregulated GPX4 in SGECs contributes to salivary secretion dysfunction in SS via the lipid ROS/pSTAT4/AQP5 axis. This study unraveled novel targets to revitalize the salivary secretion function in SS patients.

更新日期：2024-04-02

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