抑郁是一种常见的心理疾病，在全球范围内对健康和财富产生灾难性影响。关注炎症和免疫激活在抑郁症发病机制中的作用，许多尝试已经针对炎性细胞因子的阻断产生了效果，其中白细胞介素-6（IL-6）及其受体拮抗剂托西鲁单抗引起了更多关注，但其研究结果并不一致。本研究纳入中度至重度抑郁障碍（MDDD）患者，检测血清中IL-6和肿瘤坏死因子-α（TNF-α）的浓度，分析与汉密尔顿抑郁评定量表24（HAMD-24）评分的相关性，并评估其在区分MDDD患者和健康对照组中的作用。同时，采用腹腔注射脂多糖建立抑郁大鼠模型，并通过静脉注射托西鲁单抗以50 mg/kg剂量进行治疗。观察行为表现，测量血清中IL-6、TNF-α和C-反应蛋白的浓度，检测海马中IL-6和TNF-α的蛋白表达水平。观察下丘脑-垂体-肾上腺（HPA）轴的活动，并通过Western blot检测海马中的蛋白表达水平。此外，采用免疫荧光染色（IF）技术，探究IL-6和神经元（MAP2）、星形胶质细胞（GFAP）或微胶质细胞（IBA-1）的共定位。结果显示，MDDD患者和脂多糖挑战大鼠的血清IL-6水平显著增高，与HAMD-24评分或FST中的挣扎时间以及皮质酮类固醇的含量呈显著相关。ROC分析结果表明，在本研究中，IL-6在区分MDDD患者或抑郁大鼠与对照组的诊断价值显著。托西鲁单抗可以缓解脂多糖诱导的类抑郁行为，并具有血清皮质酮类固醇和下丘脑皮质释放因子（CRH）表达正常的作用。此外，托西鲁单抗可以减轻脂多糖挑战抑郁大鼠的"炎症风暴"和海马突触可塑性受损，抑制星形胶质细胞和微胶质细胞的过度活化，降低外周和中枢的IL-6、CRP和TNF-α水平，并平衡突触可塑性相关蛋白和Wnt/β-连环蛋白信号通路的关键分子在海马中的表达水平。这些结果表明，IL-6具有区分抑郁与健康对照的预测作用，并证明托西鲁单抗在脂多糖挑战抑郁大鼠中具有抗抑郁作用，针对炎症风暴和随后的海马突触可塑性损伤。 版权所有©2023 Elsevier B.V. 保留所有权利。

Depression is a common mental disease with disastrous effect on the health and wealth globally. Focusing on the role for inflammation and immune activation in the pathogenesis of depression, many tries have been taken into effect targeting at the blockage of inflammatory cytokines, among which interleukin- 6 (IL-6) and its receptor antagonist tocilizumab attracts more attention, with inconsistent findings. Moderate to severe depressive disorder (MSDD) patients were enrolled and the serum concentrations of IL-6 and tumor necrosis factor-α (TNF-α) measured, their correlation with the Hamilton Depression Rating Scale-24 (HAMD-24) scores was analyzed, and their role in discriminating MSDD patients from the health controls were evaluated. Meanwhile, a depression rat model was established by intraperitoneal injection of LPS, and tocilizumab was administrated doing 50 mg/kg via intravenous injection. The behavioral performance was observed, the serum concentration of IL-6, TNF-α, and C-reactive protein (CRP) was measured, and the protein expression of IL-6 and TNF-α in the hippocampus were also detected. The activity of the Hypothalamic-pituitary-adrenal (HPA) axis was observed, and the protein expression levels in the hippocampus were detected via western blot. Moreover, the immunofluorescence staining (IF) technique was used to investigate the co-location of IL-6 and neuron (MAP2), astrocyte (GFAP), or microglial (IBA-1). The results showed that the serum IL-6 level was significantly increased in the MSDD patients and lipopolysaccharide (LPS)-challenged rats, with a significant correlation with the HAMD-24 scores or struggling time in the FST and corticosterone (CORT) abundance. Results of ROC analysis showed a significant diagnosis value of IL-6 in discriminating MSDD patients or depression rats from the controls in the present study. Tocilizumab could relieve the depression-like behaviors induced by LPS, together with a normal abundance of serum CORT and hypothalamic CRH expression. Moreover, tocilizumab could alleviate the "inflammatory storm" and impaired hippocampal synaptic plasticity in LPS-challenged depression rats, inhibiting the hyperactivation of astrocyte and microglia, decreasing the peripheral and central abundance of IL-6, CRP, and TNF-α, and balancing the hippocampal expression levels of synaptic plasticity-associated proteins and key molecular in Wnt/β-catenin signaling pathway. These results indicated a predictive role of IL-6 in discriminating depression from controls, and demonstrated an antidepressant effect of tocilizumab in LPS-challenged rats, targeting at the inflammatory storm and the subsequent impairments of hippocampal synaptic plasticity.Copyright © 2023 Elsevier B.V. All rights reserved.