cGAS- Stimulator of Interferon Genes Signaling in Central Nervous System Disorders

Li, Fengjuan; Wang, Ningqun; Zheng, Yangmin; Luo, Yan; Zhang, Yongbo

doi:10.14336/ad.2021.0304

Cited by 20 publications

(11 citation statements)

References 182 publications

(162 reference statements)

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“…STING is a dimeric transmembrane protein at the endoplasmic reticulum (ER) with 42-kDa ( 14 ). Research on the immune role of the STING pathway in CNS disorders has grown in recent years ( 34 , 36 , 37 ). However, little is known about the role of STING in the pathological process of ischemic stroke.…”

Section: Discussionmentioning

confidence: 99%

mtDNA-STING Axis Mediates Microglial Polarization via IRF3/NF-κB Signaling After Ischemic Stroke

Kong

Chang

et al. 2022

Front. Immunol.

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Neuroinflammation is initiated in response to ischemic stroke, and is usually characterized by microglial activation and polarization. Stimulator of interferon genes (STING) has been shown to play a critical role in anti-tumor immunity and inflammatory diseases. Nevertheless, the effect and underlying mechanisms of STING on microglial polarization after ischemic stroke remain unclarified. In this study, acute ischemic stroke was simulated using a model of middle cerebral artery occlusion (MCAO) at adult male C57BL/6 mice in vivo and the BV2 microglia oxygen-glucose deprivation/reperfusion (OGD/R) model in vitro. The specific STING inhibitor C-176 was administered intraperitoneally at 30min after MCAO. We found that the expression of microglial STING was increased following MCAO and OGD/R. Pharmacologic inhibition of STING with C-176 reduced the ischemia/reperfusion (I/R)-induced brain infarction, edema and neuronal injury. Moreover, blockade of STING improved neurological performance and cognitive function and attenuated neuronal degeneration in the hippocampus after MCAO. Mechanistically, both in vivo and in vitro, we delineated that STING could promote the polarization of microglia towards the M1 phenotype and restrain M2 microglia polarization via downstream pathways, including interferon regulatory factor 3 (IRF3) and nuclear factor-κB (NF-κB). In addition, mitochondrial DNA (mtDNA), which is released to microglial cytoplasm induced by I/R injury, could facilitate microglia towards M1 modality through STING signaling pathway. Treatment with C-176 abolished the detrimental effects of mtDNA on stroke outcomes. Taken together, these findings suggest that STING, activated by mtDNA, could polarize microglia to the M1 phenotype following MCAO. Inhibition of STING may serve as a potential therapeutic strategy to mitigate neuroinflammation after ischemic stroke.

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Section: Discussionmentioning

confidence: 99%

mtDNA-STING Axis Mediates Microglial Polarization via IRF3/NF-κB Signaling After Ischemic Stroke

Kong

Chang

et al. 2022

Front. Immunol.

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“…Studies indicated that STING is an essential immune response and nociception in neurons (Flood et al, 2019;Gui et al, 2019;Liu et al, 2019a;McLaughlin et al, 2020;Donnelly et al, 2021). Studies suggested that STING contributes to ER stress and several diseases (Smith, 2020;Zhang et al, 2020;Li et al, 2021). Our data suggested that excess and prolonged elevated p-STING neutralized the ketamine-induced benefits in SNL rats.…”

Section: Discussionmentioning

confidence: 49%

Dexmedetomidine and Ketamine Attenuated Neuropathic Pain Related Behaviors via STING Pathway to Induce ER-Phagy

Liu

Kuai

Ding

et al. 2022

Front. Synaptic Neurosci.

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Our previous work indicated that ER-phagy level had altered in spinal nerve ligation (SNL) rats. In this study, we investigated whether dexmedetomidine or ketamine exhibits anti-anxiety or anti-nociceptive effects via modulation of the spinal STING/TBK pathway to alter ER-phagy in SNL rats. We evaluated the analgesic and anti-anxiety effects of ketamine and dexmedetomidine in SNL rats. 2’3’-cGAMP (a STING pathway agonist) was administrated to investigate whether enhanced spinal STING pathway activation could inhibit dexmedetomidine or ketamine treatment effects in SNL rats. Analgesic effects were assessed with the mechanical withdrawal threshold (MWT) and anti-anxiety effects were measured via an open field test (OFT). Protein expression levels were evaluated by immunoblotting. Distribution and cellular localization of Grp78 (ER stress marker) were evaluated by confocal immunofluorescence. SNL induced mechanical hypersensitivity and anxiety in rats; dexmedetomidine and ketamine both provided analgesia and anti-anxiety effects in SNL rats. Furthermore, the STING pathway was involved in the modulation of ER stress and ER-phagy in SNL rats and dexmedetomidine and ketamine alleviated ER stress by inhibiting STING pathway to enhance ER-phagy. Thus, both ketamine and dexmedetomidine provided anti-anxiety and anti-nociceptive effects by alleviating ER stress through the inhibition of the STING/TBK pathway to modulate spinal ER-phagy in SNL rats.

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“…No study has investigated which nerve cells play a main role in the activation of cGAS–STING pathways. Many studies of CNS injury suggest that microglia are the principal innate immune cells in the brain and the first responders to pathological insults and produce high levels of type I IFN [ 74 , 75 ]. Currently, most research focuses on the role of microglia in the activation of cGAS–STING pathways in CNS injury [ 76 , 77 ].…”

Section: Sting Signalling In Cns Injuriesmentioning

confidence: 99%

Emerging role of STING signalling in CNS injury: inflammation, autophagy, necroptosis, ferroptosis and pyroptosis

Zhang

et al. 2022

J Neuroinflammation

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Stimulator of interferons genes (STING), which is crucial for the secretion of type I interferons and proinflammatory cytokines in response to cytosolic nucleic acids, plays a key role in the innate immune system. Studies have revealed the participation of the STING pathway in unregulated inflammatory processes, traumatic brain injury (TBI), spinal cord injury (SCI), subarachnoid haemorrhage (SAH) and hypoxic–ischaemic encephalopathy (HIE). STING signalling is markedly increased in CNS injury, and STING agonists might facilitate the pathogenesis of CNS injury. However, the effects of STING-regulated signalling activation in CNS injury are not well understood. Aberrant activation of STING increases inflammatory events, type I interferon responses, and cell death. cGAS is the primary pathway that induces STING activation. Herein, we provide a comprehensive review of the latest findings related to STING signalling and the cGAS–STING pathway and highlight the control mechanisms and their functions in CNS injury. Furthermore, we summarize and explore the most recent advances toward obtaining an understanding of the involvement of STING signalling in programmed cell death (autophagy, necroptosis, ferroptosis and pyroptosis) during CNS injury. We also review potential therapeutic agents that are capable of regulating the cGAS–STING signalling pathway, which facilitates our understanding of cGAS–STING signalling functions in CNS injury and the potential value of this signalling pathway as a treatment target.

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cGAS- Stimulator of Interferon Genes Signaling in Central Nervous System Disorders

Cited by 20 publications

References 182 publications

mtDNA-STING Axis Mediates Microglial Polarization via IRF3/NF-κB Signaling After Ischemic Stroke

mtDNA-STING Axis Mediates Microglial Polarization via IRF3/NF-κB Signaling After Ischemic Stroke

Dexmedetomidine and Ketamine Attenuated Neuropathic Pain Related Behaviors via STING Pathway to Induce ER-Phagy

Emerging role of STING signalling in CNS injury: inflammation, autophagy, necroptosis, ferroptosis and pyroptosis

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