Zhou Fangwei, Jiang Yiting, Li Yangsong, Li Jianyao, Zhang Tian, Yu Guodong
Department of Otorhinolaryngology Head and Neck Surgery, Affiliated Hospital of Guizhou Medical University, Guiyang, 550004, China.
Guizhou Research Institute for Health Development, Guizhou Medical University, Guiyang, 550004, China.
Mol Med. 2025 Jan 9;31(1):8. doi: 10.1186/s10020-024-01057-6.
Chronic rhinosinusitis (CRS) is a global health issue, with some patients experiencing anxiety and depression-like symptoms. This study investigates the role of HMGB1 in anxiety and depression-like behaviors associated with the microglial Notch1/Hes-1 pathway in CRS mice.
A CRS mouse model was developed, and behavioral assessments were conducted to evaluate anxiety and depression-like behaviors. Techniques including F-FDG PET, Nissl staining, and immunofluorescence were used to assess hippocampal metabolic activity in CRS mice. Western Blot and RT-qPCR were employed to measure HMGB1 and Notch1/Hes-1 expression in the hippocampus, while ELISA determined inflammatory cytokine levels. The study also examined the effects of metformin on these behaviors and its mechanisms.
CRS mice exhibited increased anxiety and depression-like behaviors, accompanied by enhanced hippocampal metabolic activity. HMGB1-siRNA treatment reduced these behaviors. Hippocampal glucose metabolism was markedly higher in CRS mice than in controls. Nissl staining revealed hippocampal neuron damage, and immunofluorescence indicated microglial activation in CRS mice. Reducing HMGB1 expression inhibited Notch1/Hes-1 pathway activation. In microglia, HMGB1 knockdown suppressed the Notch1/Hes-1 pathway, reducing inflammatory cytokine secretion. Metformin improved neuropsychiatric symptoms in CRS mice by inhibiting the Notch1/Hes-1 pathway after HMGB1 downregulation.
HMGB1 activates the microglial Notch1/Hes-1 pathway in CRS mice, promoting neuroinflammation and anxiety and depression-like behaviors. Metformin alleviates these effects.
慢性鼻-鼻窦炎（CRS）是一个全球性的健康问题，一些患者会出现焦虑和抑郁样症状。本研究探讨高迁移率族蛋白B1（HMGB1）在CRS小鼠中与小胶质细胞Notch1/Hes-1通路相关的焦虑和抑郁样行为中的作用。
建立CRS小鼠模型，并进行行为评估以评价焦虑和抑郁样行为。采用包括F-FDG PET、尼氏染色和免疫荧光在内的技术评估CRS小鼠海马的代谢活性。运用蛋白质免疫印迹法（Western Blot）和逆转录定量聚合酶链反应（RT-qPCR）检测海马中HMGB1和Notch1/Hes-1的表达，同时采用酶联免疫吸附测定法（ELISA）测定炎性细胞因子水平。该研究还考察了二甲双胍对这些行为的影响及其机制。
CRS小鼠表现出焦虑和抑郁样行为增加，同时海马代谢活性增强。HMGB1小干扰RNA（siRNA）处理可减轻这些行为。CRS小鼠海马葡萄糖代谢明显高于对照组。尼氏染色显示海马神经元损伤，免疫荧光表明CRS小鼠存在小胶质细胞活化。降低HMGB1表达可抑制Notch1/Hes-1通路激活。在小胶质细胞中，敲低HMGB1可抑制Notch1/Hes-1通路，减少炎性细胞因子分泌。二甲双胍通过在HMGB1下调后抑制Notch1/Hes-1通路改善CRS小鼠的神经精神症状。
HMGB1激活CRS小鼠小胶质细胞的Notch1/Hes-1通路，促进神经炎症及焦虑和抑郁样行为。二甲双胍可减轻这些影响。
