Cathepsin C Aggravates Neuroinflammation Involved in Disturbances of Behaviour and Neurochemistry in Acute and Chronic Stress-Induced Murine Model of Depression
Cathepsin C Aggravates Neuroinflammation Involved in Disturbances of Behaviour and Neurochemistry in Acute and Chronic Stress-Induced Murine Model of Depression
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DOI：
10.1007/s11064-017-2320-y
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发表时间：
2018-01
影响因子：
4.4
通讯作者：
Yanli Zhang;Kai Fan;Yanna Liu;Gang Liu;Xiaohan Yang;Jianmei Ma
中科院分区：
文献类型：
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作者：
Yanli Zhang;Kai Fan;Yanna Liu;Gang Liu;Xiaohan Yang;Jianmei Ma
重度抑郁症被解释为一种以细胞介导的免疫激活为特征的炎症性疾病，通常由各种压力引发。小胶质细胞被认为是炎症和抑郁样行为改变之间的细胞联系。组织蛋白酶 C (Cat C) 是一种溶酶体蛋白酶，其表达主要在神经炎症中的小胶质细胞中诱导。然而，人们对 Cat C 在抑郁症病理生理学中的作用知之甚少。在本研究中，Cat C 转基因小鼠和野生型小鼠接受腹腔注射 LPS（0.5 mg/kg）和 6 周不可预测的慢性轻度应激（UCMS）暴露，建立急性和慢性应激诱导的抑郁模型。我们检查并比较了应激状态下 Cat C 差异表达小鼠的血清和抑郁目标大脑区域的行为和促炎细胞因子的变化，以及大脑中吲哚胺 2,3-双加氧酶 (IDO) 和 5-羟色胺 (5HT) 的水平。结果显示，Cat C过表达（Cat C OE）促进外周和中枢炎症反应，血清、海马和前额皮质中TNFα、IL-1β和IL-6显着增加，导致脑中IDO表达上调和5HT表达下调，从而加重旷场试验、强迫游泳试验和悬尾试验中的抑郁样行为。相比之下，Cat C 敲低（Cat C KD）部分预防了炎症，这可能有助于减轻小鼠的抑郁症状。据我们所知，我们是第一个证明 Cat C 会加重急性和慢性应激诱发的抑郁小鼠模型中行为和神经化学紊乱的神经炎症。
Major depression has been interpreted as an inflammatory disease characterized by cell-mediated immune activation, which is generally triggered by various stresses. Microglia has been thought to be the cellular link between inflammation and depression-like behavioural alterations. The expression of cathepsin C (Cat C), a lysosomal proteinase, is predominantly induced in microglia in neuroinflammation. However, little is known about the role of Cat C in pathophysiology of depression. In the present study, Cat C transgenic mice and wild type mice were subjected to an intraperitoneal injection of LPS (0.5 mg/kg) and 6-week unpredictable chronic mild stress (UCMS) exposure to establish acute and chronic stress-induced depression model. We examined and compared the behavioural and proinflammatory cytokine alterations in serum and depression-targeted brain areas of Cat C differentially expressed mice in stress, as well as indoleamine 2,3-dioxygenase (IDO) and 5-hydroxytryptamine (5HT) levels in brain. The results showed that Cat C overexpression (Cat C OE) promoted peripheral and central inflammatory response with significantly increased TNFα, IL-1β and IL-6 in serum, hippocampus and prefrontal cortex, and resultant upregulation of IDO and downregulation of 5HT expression in brain, and thereby aggravated depression-like behaviours accessed by open field test, forced swim test and tail suspension test. In contrast, Cat C knockdown (Cat C KD) partially prevented inflammation, which may help alleviate the symptoms of depression in mice. To the best of our knowledge, we are the first to demonstrate that Cat C aggravates neuroinflammation involved in disturbances of behaviour and neurochemistry in acute and chronic stress-induced murine model of depression.