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

ABSTRACT 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‐3β (GSK3β) 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 GSK3β, increased apoptosis pathways, suppressed CREB activation, and decreased BDNF. Administration of the selective GSK3β inhibitor AR‐A014418 abolished the effects of lenti‐CXCL1, and the CXCR2 inhibitor SB265610 prevented chronic stress‐induced depression‐like behaviors, inhibited GSK3β 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. FASEB J. 33, 8853–8864 (2019). www.fasebj.org