Affiliated Wuhan Mental Health Center, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430012, China; Department of Psychiatry, Wuhan Mental Health Center, Wuhan 430012, China.
Affiliated Wuhan Mental Health Center, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430012, China; Department of Psychiatry, Wuhan Mental Health Center, Wuhan 430012, China.
J Affect Disord. 2023 Aug 15;335:358-370. doi: 10.1016/j.jad.2023.05.049. Epub 2023 May 20.
Proinflammatory cytokines IL-1β has been proposed to be a key mediator in the pathophysiology of mood-related disorders. However, the IL-1 receptor antagonist (IL-1ra) is a natural antagonist of IL-1 and plays a key role in the regulation of IL-1-mediated inflammation, the effects of IL-1ra in stress-induced depression has not been well elucidated.
Chronic social defeat stress (CSDS) and lipopolysaccharide (LPS) were used to investigate the effects of IL-1ra. ELISA kit and qPCR were used to detect IL-1ra levels. Golgi staining and electrophysiological recordings were used to investigate glutamatergic neurotransmission in the hippocampus. Immunofluorescence and western blotting were used to analyze CREB-BDNF pathway and synaptic proteins.
Serum levels of IL-1ra increased significantly in two animal models of depression, and there was a significant correlation between serum IL-1ra levels and depression-like behaviors. Both CSDS and LPS induced the imbalance of IL-1ra and IL-1β in the hippocampus. Furthermore, chronic intracerebroventricular (i.c.v.) infusion of IL-1ra not only blocked CSDS-induced depression-like behaviors, but also alleviated CSDS-induced decrease in dendritic spine density and impairments in AMPARs-mediated neurotransmission. Finally, IL-1ra treatment produces antidepressant-like effects through the activation of CREB-BDNF in the hippocampus.
Further studies need to investigate the effect of IL-1ra in the periphery in CSDS-induced depression.
Our study suggests that the imbalance of IL-1ra and IL-1β reduces the expression of the CREB-BDNF pathway in the hippocampus, which dysregulates AMPARs-mediated neurotransmission, ultimately leading to depression-like behaviors. IL-1ra could be a new potential candidate for the treatment of mood disorders.
促炎细胞因子 IL-1β 被认为是与情绪相关障碍的病理生理学有关的关键介质。然而，IL-1 受体拮抗剂（IL-1ra）是 IL-1 的天然拮抗剂，在调节 IL-1 介导的炎症中起着关键作用，IL-1ra 在应激诱导的抑郁症中的作用尚未得到充分阐明。
采用慢性社交挫败应激（CSDS）和脂多糖（LPS）来研究 IL-1ra 的作用。采用 ELISA 试剂盒和 qPCR 检测 IL-1ra 水平。高尔基染色和电生理记录用于研究海马中的谷氨酸能神经传递。免疫荧光和 Western blot 用于分析 CREB-BDNF 途径和突触蛋白。
两种抑郁症动物模型中血清 IL-1ra 水平显著升高，且血清 IL-1ra 水平与抑郁样行为之间存在显著相关性。CSDS 和 LPS 均导致海马中 IL-1ra 和 IL-1β 的失衡。此外，慢性侧脑室（i.c.v.）输注 IL-1ra 不仅阻断了 CSDS 诱导的抑郁样行为，还减轻了 CSDS 诱导的树突棘密度降低和 AMPARs 介导的神经传递损伤。最后，IL-1ra 通过激活海马中的 CREB-BDNF 产生抗抑郁样作用。
进一步的研究需要调查 CSDS 诱导的抑郁症中外周 IL-1ra 的作用。
我们的研究表明，IL-1ra 和 IL-1β 的失衡降低了海马中 CREB-BDNF 途径的表达，从而使 AMPARs 介导的神经传递失调，最终导致抑郁样行为。IL-1ra 可能是治疗情绪障碍的一种新的潜在候选药物。
