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

Duan, Na; Zhang, Yanpeng; Tan, Shuwen; Sun, Jing; Ye, Mao; Gao, Hui; Pu, Kairui; Wu, Mingyan; Wang, Qiang; Zhai, Qian

doi:10.1016/j.nbd.2022.105739

Cited by 33 publications

(19 citation statements)

References 53 publications

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“…Thus, alternative agents for pruritus control are urgently required. Recently, STING agonists show efficacy in treating tumor progression, ischemic stroke, depression, and pathological pain [ 17 , 18 , 21 , 38 ]. Herein, we provide the first evidence that STING agonists (DMXAA and ADU-S100) drastically inhibits intrathecal opioid (morphine, fentanyl and sufentanil)-induced pruritus and these benefits do not come at the price of impairing optimal opioids antinociception and locomotor function.…”

Section: Discussionmentioning

confidence: 99%

“…Dysregulation of STING/IFN-I signaling causes neurotoxicity and neuroinflammation, which is a leading determinant in the neurobiology of diseases [ 41 ]. In contrast, STING-mediated IFN-I response is revealed to be protective against depression-like behaviors after chronic restraint stress and experimental autoimmune encephalomyelitis in a mouse model of multiple sclerosis [ 17 , 19 ]. Consistently, other studies also confirmed that the therapeutic properties of STING agonists on bone cancer pain, fracture-associated pain, and neuropathic pain are dependent on IFN-I signaling [ 21 , 22 ].…”

Section: Discussionmentioning

confidence: 99%

“…The production of type I interferon (IFN-I), including IFN-α and IFN-β, is a cardinal feature of STING activation via initiating and sustaining the phosphorylation of tank-binding kinase 1 (TBK1) and interferon regulatory factor 3 (IRF3) [ 16 ]. More importantly, STING activation in the central nervous system is effective against different neurological disorders through TBK1-IRF3-dependent IFN-I response and regulation of neuroinflammation [ 17 – 20 ]. Recent reports highlight that STING controls nociception in animals with pathological pain via neuron-immune modulation [ 21 , 22 ].…”

Section: Introductionmentioning

confidence: 99%

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STING controls opioid-induced itch and chronic itch via spinal tank-binding kinase 1-dependent type I interferon response in mice

Wang

Zhao

et al. 2023

J Neuroinflammation

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Background Patients receiving epidural or intrathecal opioids administration for neuraxial analgesia frequently suffer from an irritating itch. STING (stimulator of interferon genes), an innate immune modulator, is strongly implicated in pain pathogenesis via neuron-immune modulation. Given that pain and itch share some common neurocircuits, we evaluate the therapeutic potential of STING agonists in opioid-induced itch and chronic itch. Methods Opioids (morphine, fentanyl and sufentanil) were intrathecally injected to induce acute itch. Chronic itch was induced by dry skin and contact dermatitis. Opioids analgesic effect, itch-induced scratching behavior, spinal expression of STING, phosphorylation of TBK1 (tank-binding kinase 1), IRF3 (interferon regulatory factor-3) and ERK (extracellular signal-regulated kinase), as well as production of IFN-α and IFN-β were examined. STING agonists (DMXAA and ADU-S100), TBK1 inhibitor, recombinant IFN-α and IFN-β elucidated the mechanism and treatment of itch. Whole-brain functional connectivity was evaluated using resting-state fMRI. Results We report the primary expression of STING protein by the spinal dorsal horn neurons. Intraperitoneal injection of DMXAA dose-dependently reduces morphine-induced scratch bouts, without impairing morphine antinociception. Simultaneously, DMXAA alleviates fentanyl- and sufentanil-induced itching-like behavior, and chronic scratching behavior caused by dry skin and contact dermatitis. Furthermore, DMXAA drastically increases spinal phosphorylation of TBK1 and IRF3 following morphine exposure, dry skin and contact dermatitis. DMXAA-induced anti-pruritus effects and spinal productions of IFN-α and IFN-β are compensated by intrathecal delivery of the TBK1 inhibitor. Also, ADU-S100, recombinant IFN-α and IFN-β exhibits remarkable attenuation in scratching behaviors after morphine injection and dermatitis. Recombinant IFN-α inhibits morphine-induced spinal phosphorylation of ERK. Finally, DMXAA prevents dermatitis-induced the increase of cerebral functional connectivity between regions of interests such as primary somatosensory cortex, piriform cortex, retrosplenial cortex, colliculus and ventral thalamus. Conclusions STING activation confers protection against opioid-induced itch and chronic itch through spinal up-regulation of TBK1-IRF3-type I interferon cascades in mice, suggesting that STING agonists are promising candidates in translational development for pruritus relief.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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STING controls opioid-induced itch and chronic itch via spinal tank-binding kinase 1-dependent type I interferon response in mice

Wang

Zhao

et al. 2023

J Neuroinflammation

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“…22 In another study, restraint stress-induced depressive behavior was rescued by pharmacological treatment to enhance microglial phagocytosis. 23 The effects of stress on microglial phagocytosis are inconsistent. It may depend on types of stressors or brain regions.…”

Section: Discussionmentioning

confidence: 99%

“…Piirainen et al found increased CD206 + microglial synaptic phagocytosis by 10‐day restraint stress is positively correlated strengthened spatial learning 22 . In another study, restraint stress‐induced depressive behavior was rescued by pharmacological treatment to enhance microglial phagocytosis 23 . The effects of stress on microglial phagocytosis are inconsistent.…”

Section: Discussionmentioning

confidence: 99%

Preliminary analysis of hippocampus synaptic apoptosis and microglial phagocytosis induced by severe restraint stress

Enomoto

Ohgidani

Sagata

et al. 2022

Neuropsychopharm Rep

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Aim Several studies reported stress‐induced microglial phagocytosis, but the biochemical mechanisms by which stress alters microglial synaptic phagocytosis are not fully uncovered. Local or limited apoptosis without cell death was observed at neuronal synapses in previous studies, and proposed as an upstream mechanism for microglial synapse elimination. In this micro‐report, we aimed to preliminary examine local synaptic apoptosis in the mouse hippocampus following severe restraint stress, and its effect on microglial phagocytosis. Methods Mice were exposed to 10‐day water immersion restraint stress (WIRS). Brain sections including stratum lucidum in the hippocampal CA3 subfield were stained with antibodies against cleaved caspase 3, ionized calcium‐binding adapter molecule1 (Iba1), lysosomal‐associated membrane protein1 (LAMP1), vesicular glutamate transporter1 (VGLUT1). Co‐localization among these proteins were calculated. Results Our image analysis revealed that synaptic apoptosis was increased while there were no significant changes in microglial phagocytic activity and synaptic phagocytosis following 10‐day WIRS. Conclusion Severe restraint stress enhanced pre‐synaptic apoptosis in mouse CA3 stratum lucidum region, but did not promote microglial phagocytosis. The phenomenon microglia fail to phagocytose weakened and unnecessary synapses may be related to pathology of stress.

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cGAS–STING, an important signaling pathway in diseases and their therapy

Li,

Wu,

et al. 2024

MedComm

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Since cyclic guanosine monophosphate‐adenosine monophosphate synthase (cGAS)–stimulator of interferon genes (STING) signaling pathway was discovered in 2013, great progress has been made to elucidate the origin, function, and regulating mechanism of cGAS–STING signaling pathway in the past decade. Meanwhile, the triggering and transduction mechanisms have been continuously illuminated. cGAS–STING plays a key role in human diseases, particularly DNA‐triggered inflammatory diseases, making it a potentially effective therapeutic target for inflammation‐related diseases. Here, we aim to summarize the ancient origin of the cGAS–STING defense mechanism, as well as the triggers, transduction, and regulating mechanisms of the cGAS–STING. We will also focus on the important roles of cGAS–STING signal under pathological conditions, such as infections, cancers, autoimmune diseases, neurological diseases, and visceral inflammations, and review the progress in drug development targeting cGAS–STING signaling pathway. The main directions and potential obstacles in the regulating mechanism research and therapeutic drug development of the cGAS–STING signaling pathway for inflammatory diseases and cancers will be discussed. These research advancements expand our understanding of cGAS–STING, provide a theoretical basis for further exploration of the roles of cGAS–STING in diseases, and open up new strategies for targeting cGAS–STING as a promising therapeutic intervention in multiple diseases.

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

Cited by 33 publications

References 53 publications

STING controls opioid-induced itch and chronic itch via spinal tank-binding kinase 1-dependent type I interferon response in mice

STING controls opioid-induced itch and chronic itch via spinal tank-binding kinase 1-dependent type I interferon response in mice

Preliminary analysis of hippocampus synaptic apoptosis and microglial phagocytosis induced by severe restraint stress

cGAS–STING, an important signaling pathway in diseases and their therapy

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