Wu Meng, Zhao Lin, Wang Ye, Guo Qianqian, An Qi, Geng Jie, Zhang Changsheng, Guo Zhenggang
From the Department of Anesthesiology, Peking University Shougang Hospital, Beijing, China.
Anesthesia and Operation Center, The First Medical Center of Chinese PLA General Hospital, Beijing, China.
J Neuropathol Exp Neurol. 2022 Oct 18;81(11):931-942. doi: 10.1093/jnen/nlac035.
Depression is a leading cause of disability worldwide. Here, we explored the role of the HMGB1-RAGE pathway in lipopolysaccharide (LPS)-induced depression-like behavior and microglial autophagy flux, neuroinflammation, and polarization in a mouse model. Male C57BL/6 mice were infused with LPS in the abdominal cavity to induce a depression model. They then underwent testing to assess behavior and cognition. Real-time fluorescent quantitative polymerase chain reaction was used to detect the expression of the M1/M2 microglia polarization markers, HMGB1, and RAGE. Microglial activation and phenotypic transformation in the hippocampus were identified. mRFP-GFP-LC3 and Western blotting were used to detect autophagy flux in each treatment group. Finally, an LPS-induced BV2 cell model was developed to verify the involvement of the HMGB1-RAGE pathway, autophagy flux, and polarization. Ketamine improved LPS-induced depression-like behavior, inhibited the LPS-induced upregulation of HMGB1 and RAGE and the nuclear translocation of HMGB1. Moreover, ketamine reversed the blocked autophagy flux of microglia caused by LPS and regulated microglial autophagy flux through the HMGB1-RAGE pathway and microglial polarization. These results suggest that ketamine may reduce HMGB1 and RAGE accumulation in patients with depression, thereby providing a new therapeutic target for preventing and treating this disease.
抑郁症是全球范围内导致残疾的主要原因。在此，我们在小鼠模型中探究了高迁移率族蛋白B1（HMGB1）-晚期糖基化终末产物受体（RAGE）通路在脂多糖（LPS）诱导的抑郁样行为、小胶质细胞自噬通量、神经炎症及极化中的作用。将雄性C57BL/6小鼠腹腔注射LPS以诱导抑郁模型。然后对它们进行测试以评估行为和认知。采用实时荧光定量聚合酶链反应检测M1/M2小胶质细胞极化标志物、HMGB1和RAGE的表达。鉴定海马中小胶质细胞的激活和表型转化。运用mRFP-GFP-LC3和蛋白质免疫印迹法检测各治疗组的自噬通量。最后，建立LPS诱导的BV2细胞模型以验证HMGB1-RAGE通路、自噬通量和极化的参与情况。氯胺酮改善了LPS诱导的抑郁样行为，抑制了LPS诱导的HMGB1和RAGE上调以及HMGB1的核转位。此外，氯胺酮逆转了LPS导致的小胶质细胞自噬通量阻滞，并通过HMGB1-RAGE通路调节小胶质细胞自噬通量和小胶质细胞极化。这些结果表明，氯胺酮可能减少抑郁症患者体内HMGB1和RAGE的蓄积，从而为预防和治疗该疾病提供新的治疗靶点。
