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

• Published in: Neurobiology of disease Vol. 169; p. 105739
• Main Authors: Duan, Na, Zhang, Yanpeng, Tan, Shuwen, Sun, Jianyu, Ye, Mao, Gao, Hui, Pu, Kairui, Wu, Meiyan, Wang, Qiang, Zhai, Qian
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.07.2022; Elsevier
• Subjects: Animals; Chronic stress; Cytokines - metabolism; Depression - drug therapy; Depression - etiology; Interferon; Interferon Regulatory Factor-3 - metabolism; Interferon Regulatory Factor-3 - pharmacology; Membrane Proteins; Mice; Mice, Inbred C57BL; Microglia; Microglia - metabolism; Neuroinflammation; Neuroinflammatory Diseases; Phagocytosis; Protein Serine-Threonine Kinases; Neuroinflammation; Chronic stress; Interferon; Phagocytosis; Microglia
• DOI: 10.1016/j.nbd.2022.105739
• ISSN: 0969-9961; 1095-953X

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. [Display omitted] •Chronic restraint stress induces depression-like behaviours and neuroinflammation.•The number of microglia is increased and cells are activated towards a proinflammatory phenotype during chronic stress.•STING activation enhances microglial phagocytosis through STING-dependent IFN-β signalling and inhibits the production of proinflammatory cytokines in the brain.•Activation of the STING signalling pathway ameliorates depression-like behaviours during chronic stress.