Depression is associated with immune dysregulation and the aberrant activity of the hypothalamic-pituitary-adrenal (HPA) axis. However, the neurobiological molecular mechanisms underlying these associations remain unclear. c-Jun amino-terminal kinase (JNK), an important modulator in inflammation and stress responses, is often critically implicated in the development of central nervous system diseases. However, whether and how JNK mediates neuroinflammation-induced depression remains largely unknown. In this study, we investigated the role of JNK in depressive-like behaviors induced by central lipopolysaccharide (LPS) infusion. The results showed that LPS infusion led to depressive-like behaviors, accompanied by increased proinflammatory cytokine expression, increased JNK activation, and upregulated glucocorticoid receptor (GR) phosphorylation at serine 246 (pGR-Ser246) in the habenula (Hb), amygdala (Amyg) and medial prefrontal cortex (mPFC). Treatment with SP600125, a known JNK inhibitor, prevented the LPS-induced hyper-activation of JNK and alleviated depressive-like behaviors. Moreover, LPS-induced increases in the expression levels of TNF-α, IL-1β and pGR-Ser246 in these brain regions were reduced when the rats were treated with SP600125. Our results show, for the first time, that JNK activities in the Hb, Amyg, and mPFC are involved in the modulation of neuroinflammation-induced depression and participate in the regulation of the expression of proinflammatory cytokines and GR phosphorylation, which are pathological factors associated with depression. Our findings provide new insights into the mechanism of neuroinflammation-associated depression and suggest that the JNK pathway may be a potential target for treating inflammation-related depression.

中文翻译：

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抑制 JNK 可改善抑郁样行为并减少促炎细胞因子的激活和神经炎症诱导的丝氨酸 246 处糖皮质激素受体的磷酸化

抑郁症与免疫失调和下丘脑-垂体-肾上腺 (HPA) 轴的异常活动有关。然而，这些关联背后的神经生物学分子机制仍不清楚。c-Jun 氨基末端激酶 (JNK) 是炎症和应激反应的重要调节剂，通常与中枢神经系统疾病的发展密切相关。然而，JNK 是否以及如何介导神经炎症诱导的抑郁症在很大程度上仍然未知。在这项研究中，我们研究了 JNK 在中枢脂多糖 (LPS) 输注诱导的抑郁样行为中的作用。结果表明，LPS 输注导致抑郁样行为，伴随促炎细胞因子表达增加，JNK 活化增加，和上调缰核 (Hb)、杏仁核 (Amyg) 和内侧前额叶皮层 (mPFC) 中丝氨酸 246 (pGR-Ser246) 的糖皮质激素受体 (GR) 磷酸化。用已知的 JNK 抑制剂 SP600125 治疗可防止 LPS 诱导的 JNK 过度激活并减轻抑郁样行为。此外，当大鼠用 SP600125 治疗时，LPS 诱导的这些脑区域中 TNF-α、IL-1β 和 pGR-Ser246 表达水平的增加减少。我们的研究结果首次表明，Hb、Amyg 和 mPFC 中的 JNK 活性参与了神经炎症诱导的抑郁症的调节，并参与了促炎细胞因子和 GR 磷酸化的表达调节，这些都是病理相关的病理因素。与抑郁症。