The Second Affiliated Hospital of Xinxiang Medical University, Henan Mental Hospital, 453002, Xinxiang, Henan, China.
Henan Key Laboratory of Biological Psychiatry, Xinxiang Medical University, 453002, Xinxiang, Henan, China.
Transl Psychiatry. 2024 Mar 1;14(1):130. doi: 10.1038/s41398-024-02846-7.
Chronic stress is the primary environmental risk factor for major depressive disorder (MDD), and there is compelling evidence that neuroinflammation is the major pathomechanism linking chronic stress to MDD. Mitogen-activated protein kinase (MAPK) phosphatase-1 (MKP-1) is a negative regulator of MAPK signaling pathways involved in cellular stress responses, survival, and neuroinflammation. We examined the possible contributions of MKP-1 to stress-induced MDD by comparing depression-like behaviors (anhedonia, motor retardation, behavioral despair), neuroinflammatory marker expression, and MAPK signaling pathways among rats exposed to chronic unpredictable mild stress (CUMS), overexpressing MKP-1 in the hippocampus, and CUMS-exposed rats underexpressing MKP-1 in the hippocampus. Rats exposed to CUMS exhibited MKP-1 overexpression, greater numbers of activated microglia, and enhanced expressions of neuroinflammatory markers (interleukin [IL]-6, [IL]-1β, tumor necrosis factor [TNF]-ɑ, and decreased phosphorylation levels of ERK and p38 in the hippocampus as well as anhedonia in the sucrose preference test, motor retardation in the open field, and greater immobility (despair) in the forced swimming tests. These signs of neuroinflammation and depression-like behaviors and phosphorylation levels of ERK and p38 were also observed in rats overexpressing MKP-1 without CUMS exposure, while CUMS-induced neuroinflammation, microglial activation, phosphorylation levels of ERK and p38, and depression-like behaviors were significantly reversed by MKP-1 knockdown. Moreover, MKP-1 knockdown promoted the activation of the MAPK isoform ERK, implying that the antidepressant-like effects of MKP-1 knockdown may be mediated by the ERK pathway disinhibition. These findings suggested that hippocampal MKP-1 is an essential regulator of stress-induced neuroinflammation and a promising target for antidepressant development.
慢性应激是导致重度抑郁症（MDD）的主要环境风险因素，有确凿的证据表明神经炎症是将慢性应激与 MDD 联系起来的主要发病机制。丝裂原激活蛋白激酶（MAPK）磷酸酶-1（MKP-1）是一种细胞应激反应、存活和神经炎症中 MAPK 信号通路的负调节剂。我们通过比较暴露于慢性不可预测轻度应激（CUMS）、海马区过表达 MKP-1 以及海马区低表达 MKP-1 的 CUMS 暴露大鼠的抑郁样行为（快感缺失、运动迟缓、行为绝望）、神经炎症标志物表达和 MAPK 信号通路，研究了 MKP-1 对应激诱导的 MDD 的可能贡献。暴露于 CUMS 的大鼠表现出 MKP-1 过表达、更多的活化小胶质细胞以及海马区神经炎症标志物（白细胞介素 [IL]-6、[IL]-1β、肿瘤坏死因子 [TNF]-ɑ）表达增强，以及蔗糖偏好试验中的快感缺失、开阔场中的运动迟缓和强迫游泳试验中的更大不动性（绝望）。这些海马区 ERK 和 p38 的磷酸化水平以及神经炎症和抑郁样行为的标志物也在没有 CUMS 暴露的情况下过表达 MKP-1 的大鼠中观察到，而 MKP-1 敲低显著逆转了 CUMS 诱导的神经炎症、小胶质细胞活化、ERK 和 p38 的磷酸化水平以及抑郁样行为。此外，MKP-1 敲低促进了 MAPK 同工型 ERK 的激活，表明 MKP-1 敲低的抗抑郁样作用可能是通过 ERK 通路抑制的解除介导的。这些发现表明，海马区的 MKP-1 是应激诱导的神经炎症的重要调节剂，是开发抗抑郁药物的有前途的靶点。
