The chemokine CXCL1 and its receptor CXCR2 contribute to chronic stress-induced depression in mice

被引:38
作者
Chai, Hui-Hui [1 ]
Fu, Xiao-Chun [2 ]
Ma, Liang [3 ]
Sun, Hai-Tao [4 ]
Chen, Gui-Zeng [1 ]
Song, Min-Ying [1 ]
Chen, Wei-Xuan [1 ]
Chen, Yong-Sheng [1 ]
Tan, Min-Xuan [1 ]
Guo, Yan-Wu [4 ]
Li, Shao-Peng [1 ]
机构
[1] Southern Med Univ, Affiliated Dongguan Peoples Hosp, Dongguan Peoples Hosp, Dept Neurosurg, New Guchong Rd, Dongguan 523059, Peoples R China
[2] Guangdong Food & Drug Vocat Coll, Guangzhou, Guangdong, Peoples R China
[3] Suzhou Univ, Affiliated Hosp 3, Peoples Hosp Changzhou 1, Dept Gastroenterol, Suzhou, Peoples R China
[4] Southern Med Univ, Zhujiang Hosp, Dept Neurosurg, Guangzhou, Guangdong, Peoples R China
基金
中国国家自然科学基金;
关键词
UCMS; inflammation; GSK3 beta BDNF; CREB; GLYCOGEN-SYNTHASE KINASE-3; MAJOR DEPRESSION; NEUROINFLAMMATION; CYTOKINES; BRAIN; MECHANISMS; PATHOPHYSIOLOGY; BDNF; CREB; PHOSPHORYLATION;
D O I
10.1096/fj.201802359RR
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Depression is increasingly recognized as an inflammatory disease, with inflammatory crosstalk in the brain contributing its pathogenesis. Life stresses may up-regulate inflammatory processes and promote depression. Although cytokines are central to stress-related immune responses, their contribution to stress-induced depression remains unclear. Here, we used unpredictable chronic mild stress (UCMS) to induce depression-like behaviors in mice, as assessed through a suite of behavioral tests. C-X-C motif chemokine ligand 1 (CXCL1)-related molecular networks responsible for depression-like behaviors were assessed through intrahippocampal microinjection of lenti-CXCL1, the antidepressant fluoxetine, the C-X-C motif chemokine receptor 2 (CXCR2) inhibitor SB265610, and the glycogen synthase kinase-3 beta (GSK3 beta) inhibitor AR-A014418. Modulation of apoptosis-related pathways and neuronal plasticity were assessed via quantification of cleaved caspase-3, B-cell lymphoma 2-associated X protein, cAMP response element-binding protein (CREB), and brain-derived neurotrophic factor (BDNF) protein expression. CXCL1/CXCL2 expression was correlated with depression-like behaviors in response to chronic stress or antidepressant treatment in the UCMS depression model. Intrahippocampal microinjection of lenti-CXCL1 increased depression-like behaviors, activated GSK3 beta, increased apoptosis pathways, suppressed CREB activation, and decreased BDNF. Administration of the selective GSK3 beta inhibitor AR-A014418 abolished the effects of lenti-CXCL1, and the CXCR2 inhibitor SB265610 prevented chronic stress-induced depression-like behaviors, inhibited GSK3 beta activity, blocked apoptosis pathways, and restored BDNF expression. The CXCL1/CXCR2 axis appears to play a critical role in stress-induced depression, and CXCR2 is a potential novel therapeutic target for patients with depression.-Chai, H.-H., Fu, X.-C., Ma, L., Sun, H.-T., Chen, G.-Z., Song, M.-Y., Chen, W.-X., Chen, Y.-S., Tan, M.-X., Guo, Y.-W., Li, S.-P. The chemokine CXCL1 and its receptor CXCR2 contribute to chronic stress-induced depression in mice.
引用
收藏
页码:8853 / 8864
页数:12
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