Department of Neurology, Huashan Hospital, Fudan University, No. 12 Wulumuqi Zhong Road, Shanghai, 200040, China.
Neurochem Res. 2018 May;43(5):985-994. doi: 10.1007/s11064-018-2504-0. Epub 2018 Mar 24.
Inflammation recently has been considered to be participated in the pathogenesis of major depressive disorder (MDD). However, the detailed mechanism of inflammation in depression has not been completely understood yet. In the present study, depression mice model was established by chronic social defeat stress (CSDS) method and confirmed by behavior examinations including forced swimming test and sucrose preference test. The decrease of spine density and postsynaptic density protein 95 (PSD95) in hippocampus further verified the depression model. Then, the microglia polarization state and endoplasmic reticulum (ER) stress were investigated. At transcriptional level, M1 marker (inducible nitric oxide synthase (iNOS), CD16, CD86, CXCL10) in CSDS mice was higher than that in control group while there was no difference in M2 marker (Arginase and CD206) between two groups. And it was observed in the hippocampus of CSDS induced depression mice that increased activated microglia was merged with iNOS instead of arginase by immunofluorescence staining. Furthermore, the M1 marker Interleukin (IL)-1β and tumor necrosis factor (TNF)-α were increased in depression mice while the M1 marker IL-6 and M2 marker IL-10 remained unchanged. The expression of ER stress signaling factors, including protein kinase RNA-like ER kinase (PERK), Phosphorylated α-subunit of eukaryotic translation initiation factor 2(p-eIF2α), C/EBP homologous protein (CHOP), and X-box binding protein 1(XBP1) were significantly higher in CSDS-induced depression mice than in control mice. In all, our results suggest that M1 polarization and ER stress play a vital role in MDD pathogenesis.
炎症最近被认为参与了重度抑郁症（MDD）的发病机制。然而，炎症在抑郁症中的详细机制尚未完全了解。在本研究中，通过慢性社交挫败应激（CSDS）方法建立了抑郁小鼠模型，并通过强迫游泳试验和蔗糖偏好试验等行为检查进行了确认。海马体中树突棘密度和突触后密度蛋白 95（PSD95）的减少进一步验证了抑郁模型。然后，研究了小胶质细胞极化状态和内质网（ER）应激。在转录水平上，CSDS 小鼠的 M1 标志物（诱导型一氧化氮合酶（iNOS）、CD16、CD86、CXCL10）高于对照组，而两组间的 M2 标志物（精氨酸酶和 CD206）无差异。免疫荧光染色观察到 CSDS 诱导的抑郁小鼠海马体中，激活的小胶质细胞与 iNOS 而非精氨酸酶融合。此外，抑郁小鼠中 M1 标志物白细胞介素（IL）-1β和肿瘤坏死因子（TNF）-α增加，而 M1 标志物 IL-6 和 M2 标志物 IL-10 保持不变。ER 应激信号转导因子的表达，包括蛋白激酶 RNA 样内质网激酶（PERK）、真核翻译起始因子 2 的磷酸化α亚基（p-eIF2α）、C/EBP 同源蛋白（CHOP）和 X 盒结合蛋白 1（XBP1）在 CSDS 诱导的抑郁小鼠中明显高于对照组。总之，我们的结果表明 M1 极化和 ER 应激在 MDD 的发病机制中起着重要作用。
