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

Abstract

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.

TAK1 deficiency promotes liver injury and tumorigenesis via ferroptosis and macrophage cGAS-STING signalling

“… 65 However, STING signalling plays a crucial role in numerous forms of cell death, including ferroptosis. 66 , 67 Moreover, co-immunoprecipitation studies demonstrated that STING could interact with the TAK1 protein, indicating an interaction between STING and TAK1. 68 However, the relationship between STING expression and TAK1 expression in human diseases remains unclear.…”

Activation of endogenous retrovirus triggers microglial immuno-inflammation and contributes to negative emotional behaviors in mice with chronic stress

“…Recently, cytosolic immunogenic nucleic acids sensing, for instance cGAS–STING pathway, has been increasingly recognized as a primary determinant and potent regulator in neuroimmunological diseases, neurological infections, neurodegenerative diseases, as well as neuro-oncology [ 46 – 51 ]. Endoplasmic reticulum protein STING can be bound and activated by cytosolic nucleic acids sensor cGAS, and then lead to a complex intracellular signaling cascade and nuclear translocation of transcription factors, such as NF-κB, that stimulate the production of various pro-inflammatory molecules, including cytokines, chemokines, type I interferons (IFNs) [ 52 , 53 ]. Previous studies have observed the activation of microglial cGAS–STING pathway in exogenous viral infections, traumatic brain injury, cerebral ischemic stroke, and Alzheimer's disease [ 50 , 54 – 57 ], however, the activators of cGAS–STING pathway were come from exogenous virus or extracellular nucleic acids released by damaged or dead cells that phagocytized by microglia.…”

Molecular mechanisms of neuronal death in brain injury after subarachnoid hemorrhage

“… Wang et al (2012) reported that a small amount of autophagy exists in normal brain neurons; however, it is activated in large quantities after SAH. Autophagy can improve cerebral oedema, protect the blood-brain barrier, reduce cortical neuronal apoptosis and improve clinical prognosis after intervention with rapamycin (RAP) and 3-methyladenine (3-MA) ( Hu X. et al, 2022 ; Pang et al, 2022 ). Lu et al reported that melatonin enhances autophagy in brain vessel endothelial cells, then protect blood-brain barrier integrity.…”