The chemokine CXCL1 and its receptor CXCR2 contribute to chronic stress-induced depression in mice
The chemokine CXCL1 and its receptor CXCR2 contribute to chronic stress-induced depression in mice
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趋化因子 CXCL1 及其受体 CXCR2 会导致小鼠慢性应激诱发的抑郁症。
DOI：
10.1096/fj.201802359rr
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发表时间：
2019-08-01
期刊：
影响因子：
4.8
通讯作者：
Li, Shao-Peng
中科院分区：
文献类型：
--
作者：
Chai, Hui-Hui;Fu, Xiao-Chun;Li, Shao-Peng
抑郁症越来越被认为是一种炎症性疾病，大脑中的炎症串扰参与了其发病机制。生活压力可能会上调炎症过程，促进抑郁。尽管细胞因子是应激相关免疫反应的中心，但它们在应激诱导的抑郁中的作用尚不清楚。在这里，我们使用不可预测的慢性温和应激(UCMS)来诱导小鼠的抑郁样行为，通过一系列行为测试进行评估。通过海马区微量注射Lenti-CXCL1、抗抑郁剂氟西汀、C-X-C基序趋化因子受体2(CXCR2)抑制剂SB265610和糖原合成酶激酶-3β(GSK3β)抑制剂AR-A014418，评估与抑郁行为有关的C-X-C基序趋化因子配体1(CXCL1)相关分子网络。通过定量caspase-3、B细胞淋巴瘤相关X蛋白、cAMP反应元件结合蛋白(CREB)和脑源性神经营养因子(BDNF)蛋白的表达来评价细胞凋亡相关通路的调控和神经元的可塑性。在UCMS抑郁模型中，CXCL1/CXCL2的表达与慢性应激或抗抑郁药物治疗反应中的抑郁样行为相关。海马区微量注射Lenti-CXCL1可增加抑郁样行为，激活GSK3β，增加细胞凋亡途径，抑制CREB激活，减少BDNF。给予选择性GSK3β抑制剂AR-A014418可阻断Lenti-CXCL1的作用，CXCR2抑制剂SB265610可预防慢性应激诱导的抑郁样行为，抑制GSK3β活性，阻断细胞凋亡途径，恢复BDNF的表达。CXCL1/CXCR2轴似乎在应激诱导的抑郁中起着关键作用，CXCR2是一种潜在的治疗抑郁症患者的新靶点。-Chai，H.H.，Fu，X.-C.，Ma，L.，Sun，H.T.，Chen，G.Z.，Song，My-Y.，Chen，W.X.，Chen，Y.-S.，Tan，M.X.，Guo，Y.-W.，Li，S.P.趋化因子CXCL1及其受体CXCR2在慢性应激诱导的小鼠抑郁中起作用。
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.