Therapeutic targeting of STING-TBK1-IRF3 signalling ameliorates chronic stress induced depression-like behaviours by modulating neuroinflammation and microglia phagocytosis
Therapeutic targeting of STING-TBK1-IRF3 signalling ameliorates chronic stress induced depression-like behaviours by modulating neuroinflammation and microglia phagocytosis
复制标题
STING-TBK1-IRF3 信号传导的治疗靶向通过调节神经炎症和小胶质细胞吞噬作用改善慢性应激诱导的抑郁样行为
DOI：
10.1016/j.nbd.2022.105739
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发表时间：
2022-04-25
影响因子：
6.1
通讯作者：
Zhai, Qian
中科院分区：
文献类型：
--
作者：
Duan, Na;Zhang, Yanpeng;Zhai, Qian
众所周知，压力会导致神经和精神疾病的发生。在中枢神经系统中，STING（干扰素基因刺激剂）在调节免疫反应中的作用已被广泛认为，并且这种蛋白质具有神经毒性和神经保护特性。然而，STING 信号通路的潜在作用及其在慢性应激中的潜在调节机制尚未明确。在本研究中，C57BL/6小鼠受到间歇性束缚应激14天（6小时/天），并对慢性束缚应激（RST）小鼠进行蔗糖偏好、高架十字迷宫和悬尾试验。在这里，我们发现 RST 小鼠表现出类似抑郁的行为，并伴有大脑中促炎细胞因子水平的增加。我们还观察到 RST 小鼠海马体和前额皮质中通路成分 STING、p-TBK1（磷酸化 TANK 结合激酶-1）和 p-IRF3（磷酸化干扰素调节因子-3）的水平显着降低。在 RST 小鼠的海马体和前额皮质中也观察到 STING 荧光强度显着降低。接下来，利用荧光标记乳胶珠、流式细胞术和CD68阳性细胞计数来评估小胶质细胞体内和体外的吞噬能力。重要的是，我们的结果首先表明，通过给予 STING 激动剂 2'3-cGAMP 激活 STING 通路，可以增强小胶质细胞的吞噬作用，并抑制 RST 小鼠大脑中促炎细胞因子 TNF-α、IL-6 和 IL-1 β 的释放，从而进一步产生抗抑郁作用。根据我们的研究结果，通过激活 STING 通路来改善压力驱动的抑郁样行为与抑制神经炎症和增强吞噬作用有关。
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 sub-jected 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-alpha, IL-6, and IL-1 beta 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.