State Key Laboratory of Chemical Oncogenomics, School of Chemical Biology and Biotechnology, Peking University Shenzhen Graduate School, Shenzhen, 518055, China.
College of Forensic Medicine, Institute of Forensic Injury, Xi'an Jiaotong University Health Science Center, Xi'an, Shanxi, China.
Cell Commun Signal. 2024 Sep 2;22(1):427. doi: 10.1186/s12964-024-01796-3.
Depression is often linked to inflammation in the brain. Researchers have been exploring ways to reduce this inflammation to improve depression symptoms. One potential target is a protein called RIPK1, which is known to contribute to brain inflammation. However, it's unclear how RIPK1 influences depression. Our study aims to determine whether RIPK1 inhibition could alleviate neuroinflammation-associated depression and elucidate its underlying mechanisms.
To investigate our research objectives, we established a neuroinflammation mouse model by administering LPS. Behavioral and biochemical assessments were conducted on these mice. The findings were subsequently validated through in vitro experiments.
Using LPS-induced depression models, we investigated RIPK1's role, observing depressive-like behaviors accompanied by elevated cytokines, IBA-1, GFAP levels, and increased inflammatory signaling molecules and NO/HO. Remarkably, Necrostatin (Nec-1 S), a RIPK1 inhibitor, mitigated these changes. We further found altered expression and phosphorylation of eIF4E, PI3K/AKT/mTOR, and synaptic proteins in hippocampal tissues, BV2, and N2a cells post-LPS treatment, which Nec-1 S also ameliorated. Importantly, eIF4E inhibition reversed some of the beneficial effects of Nec-1 S, suggesting a complex interaction between RIPK1 and eIF4E in LPS-induced neuroinflammation. Moreover, citronellol, a RIPK1 agonist, significantly altered eIF4E phosphorylation, indicating RIPK1's potential upstream regulatory role in eIF4E and its contribution to neuroinflammation-associated depression.
These findings propose RIPK1 as a pivotal mediator in regulating neuroinflammation and neural plasticity, highlighting its significance as a potential therapeutic target for depression.
抑郁症通常与大脑中的炎症有关。研究人员一直在探索减少这种炎症以改善抑郁症状的方法。一种潜在的靶点是一种叫做 RIPK1 的蛋白质，它已知会导致大脑炎症。然而，RIPK1 如何影响抑郁还不清楚。我们的研究旨在确定 RIPK1 抑制是否可以缓解与神经炎症相关的抑郁，并阐明其潜在机制。
为了研究我们的研究目标，我们通过给予 LPS 建立了一个神经炎症小鼠模型。对这些小鼠进行了行为和生化评估。随后通过体外实验验证了这些发现。
使用 LPS 诱导的抑郁模型，我们研究了 RIPK1 的作用，观察到伴有细胞因子、IBA-1、GFAP 水平升高以及炎症信号分子和 NO/HO 增加的抑郁样行为。值得注意的是，RIPK1 抑制剂 Necrostatin (Nec-1 S) 减轻了这些变化。我们还发现，LPS 处理后海马组织、BV2 和 N2a 细胞中 eIF4E、PI3K/AKT/mTOR 和突触蛋白的表达和磷酸化发生改变，Nec-1 S 也改善了这些改变。重要的是，eIF4E 抑制逆转了 Nec-1 S 的一些有益作用，表明 RIPK1 和 eIF4E 之间在 LPS 诱导的神经炎症中存在复杂的相互作用。此外，RIPK1 激动剂香茅醇显著改变了 eIF4E 的磷酸化，表明 RIPK1 可能在 eIF4E 的上游调节其作用，并参与与神经炎症相关的抑郁。
这些发现表明 RIPK1 是调节神经炎症和神经可塑性的关键介质，强调了它作为治疗抑郁症的潜在治疗靶点的重要性。
