STAT3 activation in microglia exacerbates hippocampal neuronal apoptosis in diabetic brains

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. We demonstrated that signal transducer and activator of transcription 3 (STAT3) activation in microglia exacerbates neuronal apoptosis of the diabetic hippocampus and that increased tumor necrosis factor‐α (TNF‐α) through STAT3 activation causes neuronal apoptosis. We also took the advantage of mice lacking STAT3 in microglia and demonstrated that depletion of microglial STAT3 reduced neuronal apoptosis in the diabetic hippocampus. There 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.