CTRP3 acts as a novel regulator in depressive-like behavior associated inflammation and apoptosis by meditating p38 and JNK MAPK signaling
CTRP3 acts as a novel regulator in depressive-like behavior associated inflammation and apoptosis by meditating p38 and JNK MAPK signaling
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DOI：
10.1016/j.biopha.2019.109489
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发表时间：
2019-12-01
影响因子：
7.5
通讯作者：
Luo, Li-Ling
中科院分区：
文献类型：
--
作者：
Meng, Jing;Wang, Dong-Ming;Luo, Li-Ling
抑郁症是一种复杂的病因模式，其病理和有效治疗方法非常有限。C1q-肿瘤坏死因子相关蛋白-3(CTRP3)是一种脂肪因子，在代谢调节特性中发挥关键作用。然而，CTRP3对抑郁症的影响在很大程度上是未知的。在本研究中，我们发现慢性不可预知的轻度应激(CUMS)所致抑郁小鼠的海马区CTRP3表达水平显著降低。在抑郁小鼠模型中，CTRP3基因缺陷的小鼠加重了抑郁相关行为，表现为运动活动和蔗糖消耗减少，而在尾部悬挂试验(TST)和强迫游泳试验(FST)中不动时间增加。此外，CTRP3基因敲除显著加速了CUMS诱导的神经元死亡和裂解Caspase-3表达的增加。此外，CTRP3缺失增强了暴露于CUMS的小鼠的促炎反应，这与核因子-kappa B(NF-kappa B)信号的激活有关。CTRP3基因敲除小鼠暴露于CUMS后，海马区p38和JNK等丝裂原活化蛋白激酶(MAPKs)活性进一步增强。相反，CTRP3过表达在脂多糖(LPS)处理的小胶质细胞中显示出抗凋亡和抗炎的作用。重要的是，体外实验表明，通过阻断脂多糖刺激的小胶质细胞中的p38和JNK信号通路，CTRP3基因敲除加重的细胞凋亡和炎症反应被显著地取消。接下来，在CUMS暴露的CTRP3缺乏的小鼠中，抑制p38和JNK显著减轻抑郁样行为、海马神经元死亡、细胞凋亡和炎症。因此，CTRP3可能通过调节p38和JNK信号通路，成为治疗抑郁症的新靶点。
Depression is a complicated etiological pattern, and its pathology and effective treatments are highly limited.C1q-tumor necrosis factor-related protein-3 (CTRP3) is an adipokine, playing crucial roles in metabolic regulatory properties. However, the effects of CTRP3 on depression are largely unknown. In the present study, we found that CTRP3 expression levels were markedly reduced in hippocampus of mice with depression induced by chronic unpredictable mild stress (CUMS). In mouse model with depression, CTRP3-deficient mice aggravated depression-associated behaviors, as evidenced by the reduced locomotor activity and sucrose consumption, while the elevated immobility time in the tail suspension test (TST) and forced swimming test (FST). Moreover, CUMS-induced neuron death and increased expression of cleaved Caspase-3 were significantly accelerated by CTRP3 knockout. Furthermore, CTRP3 deletion intensified pro-inflammatory response in CUMS-exposed mice, which was associated with the activation of nuclear factor-kappa B(NF-kappa B) signaling. The activity of mitogen-activated protein kinases (MAPKs), including p38 and JNK, was further promoted in hippocampus of CTRP3-knockout mice with CUMS exposure. In contrast,CTRP3 over-expression showed anti-apoptotic and anti-inflammatory effects in lipopolysaccharide (LPS)-treated microglial cells. Importantly, the in vitro experiments demonstrated that CTRP3 knockdown-exacerbated apoptosis and inflammatory response were remarkably abrogated by the blockage of p38 and JNK signaling pathways in microglia stimulated by LPS. Next, in CUMS exposed mice with CTRP3 deficiency, suppressing p38 and JNK markedly alleviated depressive-like behavior, hippocampal neuron death, apoptosis and inflammation. Therefore, CTRP3 may be an innovative therapeutic target for treating patients with depression through regulating p38 and JNK signaling.