JMJD3和TLR4调控应激致抑郁障碍易感性

Exposure to stressful event during development has been shown to produce genetic modification and results in long-lasting alternations of neural plasticity and neuroendocrine immune dysfunction, which increases vulnerability to depression induced by stress. In the previous study, we found that stress induced depressive like behaviours, microglial activation and higher levels of cytokines in hippocampus. Stress induced depressive like behaviours and obvious TLR4-NF-κB activation in hippocampus of both depressive and obesity animals. Another study demonstrated that Jmjd3 is essential for the epigenetic modulation of microglia phenotypes and M1 microglia polarization results in higher level of cytokines. These studies suggest that Jmjd3 and TLR4 may be the key regulatory factors for susceptibility to depression. The present study will build juvenile and adult depression animal model using chronic unpredictable mild stress, meanwhile suppress microglial activation, regulate H3K27me3 level and inhibit TLR4 activation, as well as assess the activation mode of microglia, the level of TLR4 activation and cytokines expression in prefrontal cortex and hippocampus. The aim of the study is to clarify the roles of JMJD3 expression and TLR4 activation of microglia and the occurrence of central inflammatory state in depression and the vulnerability to depression.

发育期应激通过表观遗传修饰影响神经可塑性、导致持久的神经内分泌免疫紊乱，增加抑郁障碍易感性。我们发现，应激致抑郁动物海马小胶质细胞激活、炎性细胞因子增加；应激致抑郁和应激致肥胖动物抑郁时均出现TLR4-NF-κB明显激活。另有研究发现，Jmjd3调控小胶质细胞激活表型，毒性（M1型）激活导致炎性细胞因子分泌增加。以上研究提示，Jmjd3和TLR4可能是中枢炎症致抑郁障碍易感性的调控因子。本研究采用慢性不可预期性应激建立青少年和成年期抑郁模型动物，以米诺环素抑制小胶质细胞活化，以Jmjd3抑制剂和H3K27me3甲基转移酶抑制剂调节H3K27me3去甲基化水平，以TLR4拮抗剂抑制TLR4通路激活。观察海马和前额叶小胶质细胞活化状态与活化模式、TLR4通路活化指标、细胞因子表达水平与抑郁样行为的关系。阐明小胶质细胞JMJD3表达和TRL4激活在抑郁障碍发生机制及易感性中的作用。

免疫系统激活和神经炎症状态可能是抑郁症发病机制之一和治疗的潜在靶点。而早年应激经历可增加抑郁症发病易感性，但其与神经炎症的关系尚不清楚。Jmjd3是一个特异降解抑制性标记物H3K27me3的组蛋白去甲基化酶，Jmjd3调控小胶质细胞激活状态并通过增强促炎性细胞因子的转录参与众多炎性反应进程，提示Jmjd3可能是介导小胶质细胞激活和炎性细胞因子表达的关键调控因子。本研究聚焦早年应激经历致神经炎症在抑郁障碍发生和易感性增加中的机制和表观遗传调控。研究系统考察了慢性不可预期性应激、母婴分离应激、脂多糖注射动物模型前额叶和海马中小胶质细胞激活表型、促炎性细胞因子水平、NF-κB、Jmjd3以及H3K27me3表达变化。研究发现，Jmjd3和H3K27me3通过调节小胶质细胞M1激活和促炎性细胞因子的表达参与早年应激致抑郁障碍易感性；中枢小胶质细胞的M1极化表型和TLR4-NF-κB激活参与早年应激和肥胖导致的抑郁障碍易感性发生；EZH2靶向调节H3K27me3水平，参与调控小胶质细胞的激活、极化和神经炎症发生；PPARγ参与介导小胶质细胞激活表型，脂联素（adiponectin，APN）影响EZH2和H3K27me3的结合。以上机制均与应激致抑郁障碍易感性改变有关。在干预方法上，发现米诺环素、GSK-J4和吡格列酮可通过抑制小胶质细胞激活、拮抗Jmjd3和激活PPARγ减轻神经炎症状态和缓解抑郁样行为，提示靶向减轻小胶质细胞炎性激活和降低神经炎症的治疗可能是抑郁症治疗的新的方向。