Department of Veterinary Pharmacology, College of Veterinary Medicine and Institute of Veterinary Science, Kangwon National University, Gangwondo, Republic of Korea.
Department of Biomedical Sciences and Pharmacology, College of Medicine, Seoul National University, Seoul, Republic of Korea.
J Cell Physiol. 2021 Oct;236(10):7058-7070. doi: 10.1002/jcp.30373. Epub 2021 Mar 23.
Diabetes mellitus (DM) characterized by hyperglycemia leads to a variety of complications, including cognitive impairment or memory loss. The hippocampus is a key brain area for learning and memory and is one of the regions that is most sensitive to diabetes. However, the pathogenesis of diabetic neuronal lesion is not yet completely understood. We focused on the association of microglia activation and brain lesions in diabetes. In this study, we investigated whether and how signal transducer and activator of transcription 3 (STAT3) activation in microglia affects neuronal lesions in diabetic brains. Using a streptozotocin-induced type 1 DM model, we showed enhanced hippocampal neuronal apoptosis that was associated with increased STAT3 activation. We found that hyperglycemia increased the expression of inflammatory cytokines such as interferon-γ (IFN-γ) and interleukin-6, in the diabetic hippocampus. In particular, IFN-γ induced autocrine activation of microglia, and STAT3 activation is important for this process. We also demonstrated that STAT3 activation in microglia increased tumor necrosis factor-α (TNF-α) expression; subsequently, TNF-α increased neuronal apoptosis by increasing reactive oxygen species (ROS) levels in the neuronal cells. We also took advantage of mice lacking STAT3 in microglia and demonstrated that depletion of microglial STAT3 reduced neuronal apoptosis in the diabetic hippocampus. Taken together, these results suggest that STAT3 activation in microglia plays an important role in hyperglycemia-induced neuronal apoptosis in the diabetic hippocampus and provide a potential therapeutic benefit of STAT3 inhibition in microglia for preventing diabetic neuronal lesions.
糖尿病（DM）以高血糖为特征，导致多种并发症，包括认知障碍或记忆力减退。海马体是学习和记忆的关键大脑区域，也是对糖尿病最敏感的区域之一。然而，糖尿病性神经元损伤的发病机制尚不完全清楚。我们专注于小胶质细胞激活与糖尿病脑损伤的关联。在这项研究中，我们研究了小胶质细胞中信号转导和转录激活因子 3（STAT3）的激活是否以及如何影响糖尿病大脑中的神经元损伤。使用链脲佐菌素诱导的 1 型糖尿病模型，我们显示增强的海马神经元凋亡与 STAT3 激活增加有关。我们发现高血糖增加了糖尿病海马体中炎症细胞因子（如干扰素-γ（IFN-γ）和白细胞介素-6）的表达。特别是，IFN-γ诱导小胶质细胞的自分泌激活，而 STAT3 激活对于该过程很重要。我们还表明，小胶质细胞中的 STAT3 激活增加肿瘤坏死因子-α（TNF-α）的表达；随后，TNF-α 通过增加神经元细胞中的活性氧（ROS）水平来增加神经元凋亡。我们还利用缺乏小胶质细胞中 STAT3 的小鼠，并证明小胶质细胞 STAT3 的耗竭减少了糖尿病海马体中的神经元凋亡。总之，这些结果表明小胶质细胞中的 STAT3 激活在高血糖诱导的糖尿病海马体神经元凋亡中起重要作用，并为 STAT3 抑制在小胶质细胞中预防糖尿病性神经元损伤提供了潜在的治疗益处。
