Therapeutic targeting of STING-TBK1-IRF3 signalling ameliorates chronic stress induced depression-like behaviours by modulating neuroinflammation and microglia phagocytosis

促炎细胞因子 小胶质细胞 神经炎症 干扰素基因刺激剂 TLR4型 药理学 内部收益率3 医学 海马体 吞噬作用 免疫学 内分泌学 炎症 免疫系统 先天免疫系统 航空航天工程 工程类
作者
Na Duan,Yanpeng Zhang,Shuwen Tan,Jing Sun,Mao Ye,Hui Gao,Kairui Pu,Ming‐Yan Wu,Qiang Wang,Qian Zhai
出处
期刊:Neurobiology of Disease [Elsevier]
卷期号:169: 105739-105739 被引量:23
标识
DOI:10.1016/j.nbd.2022.105739
摘要

Stress is well known to contribute to the development of both neurological and psychiatric diseases. In the central nervous system, a role for STING (stimulator of interferon genes) in modulating immunological responses has been widely suggested, and this protein possesses both neurotoxic and neuroprotective properties. However, the potential role of the STING signalling pathway and the underlying regulatory mechanism in chronic stress have not been well established. In this study, C57BL/6 mice were subjected to intermittent restraint stress for 14 days (6 h/day), and sucrose preference, elevated plus maze, and tail suspension tests were performed by mice subjected to chronic restraint stress (RST). Here, we showed that RST mice displayed depression-like behaviours, accompanied by increased levels of proinflammatory cytokines in the brain. We also observed remarkably decreased levels of the pathway components STING, p-TBK1 (phospho-TANK-binding kinase-1), and p-IRF3 (phospho-interferon regulatory factor-3) in the hippocampus and the prefrontal cortex of RST mice. Significant reductions in STING fluorescence intensity were also observed in the hippocampus and the prefrontal cortex of RST mice. Next, fluorescently labelled latex beads, flow cytometry, and CD68-positive cell counts were utilized to evaluate the phagocytic abilities of microglia in vivo and in vitro. Importantly, our results first indicated that activation of the STING pathway by administration of the STING agonist 2'3-cGAMP enhanced microglial phagocytosis and suppressed the release of the proinflammatory cytokines TNF-α, IL-6, and IL-1β in the brains of RST mice, which further led to antidepressant effects. Based on the results of our study, the amelioration of stress-driven depression-like behaviours by activation of the STING pathway is associated with the suppression of neuroinflammation and enhanced phagocytosis.
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