cGAS-STING pathway aggravates early cerebral ischemia-reperfusion injury in mice by activating NCOA4-mediated ferritinophagy

Li, Bingyu; Wang, Wei; Li, Yanan; Wang, Su; Liu, Hengjuan; Xia, Zhongyuan; Gao, Wenwei; Zhao, Bo

doi:10.1016/j.expneurol.2022.114269

Cited by 28 publications

(15 citation statements)

References 51 publications

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“…The synergistic action of TNF‐α signaling through TNFRI and type I IFN activation, in the absence of active caspase 8, can trigger a form of cell death called necroptosis or programmed necrosis (Bertheloot et al, 2021). The cGAS‐STING axis is activated in microglia and neurons as detected 3–7 days after brain ischemia, and inhibition of this pathway induced an anti‐inflammatory phenotype in microglia, reduced neuronal cell death and infarct volume, and improved the neurological function (Jiang et al, 2021; Kong et al, 2022; Li et al, 2020; Li et al, 2023; Ma et al, 2020). Single‐cell transcriptomics identified small populations of inflammatory and IFN‐responsive microglia in the aged brain (Hammond et al, 2019).…”

Section: Intracellular Mediators Of Danger Signal Receptor Activationmentioning

confidence: 99%

“…Further, dysfunctional foam cells accumulating in the injured brain tissue after stroke (Becktel et al, 2022; Chung et al, 2018) may promote cognitive decline, as recently reviewed (Zbesko et al, 2023). In the aged brain, the impaired reparative mechanisms (Gallizioli et al, 2020; Jin et al, 2023; Li et al, 2023) and the increased lipid‐laden microglia (Arbaizar‐Rovirosa et al, 2023) may favor post‐stroke cognitive impairment (Rost et al, 2022). Altogether, it is plausible that microglia play a role in the intricate immune‐mediated processes associated with the enduring cognitive consequences of ischemic stroke (Doyle & Buckwalter, 2020; Endres et al, 2022).…”

Section: Long‐term Consequences Of Dysfunctional Microglia After Strokementioning

confidence: 99%

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Role of microglia in stroke

Planas

2024

Glia

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Microglia play key roles in the post‐ischemic inflammatory response and damaged tissue removal reacting rapidly to the disturbances caused by ischemia and working to restore the lost homeostasis. However, the modified environment, encompassing ionic imbalances, disruption of crucial neuron–microglia interactions, spreading depolarization, and generation of danger signals from necrotic neurons, induce morphological and phenotypic shifts in microglia. This leads them to adopt a proinflammatory profile and heighten their phagocytic activity. From day three post‐ischemia, macrophages infiltrate the necrotic core while microglia amass at the periphery. Further, inflammation prompts a metabolic shift favoring glycolysis, the pentose‐phosphate shunt, and lipid synthesis. These shifts, combined with phagocytic lipid intake, drive lipid droplet biogenesis, fuel anabolism, and enable microglia proliferation. Proliferating microglia release trophic factors contributing to protection and repair. However, some microglia accumulate lipids persistently and transform into dysfunctional and potentially harmful foam cells. Studies also showed microglia that either display impaired apoptotic cell clearance, or eliminate synapses, viable neurons, or endothelial cells. Yet, it will be essential to elucidate the viability of engulfed cells, the features of the local environment, the extent of tissue damage, and the temporal sequence. Ischemia provides a rich variety of region‐ and injury‐dependent stimuli for microglia, evolving with time and generating distinct microglia phenotypes including those exhibiting proinflammatory or dysfunctional traits and others showing pro‐repair features. Accurate profiling of microglia phenotypes, alongside with a more precise understanding of the associated post‐ischemic tissue conditions, is a necessary step to serve as the potential foundation for focused interventions in human stroke.

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Section: Intracellular Mediators Of Danger Signal Receptor Activationmentioning

confidence: 99%

Section: Long‐term Consequences Of Dysfunctional Microglia After Strokementioning

confidence: 99%

Role of microglia in stroke

Planas

2024

Glia

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“…The release of free iron after erythrocyte lysis and from ferritin stores may influence oxidative stress, glutamine release, and inflammation after hemorrhagic brain injury. Nuclear receptor coactivator 4 (NCOA4) mediates ferritin degradation via the autophagosome-lysosome pathway through ferritinophagy ( Li B. et al, 2023 ). With the help of the autophagy proteins ULK112 and FIP200, Tax1-binding protein 1 binds directly to NCOA4 and promotes ferritin lysosomal localization and degradation under iron-depleted conditions ( Zheng et al, 2021b ).…”

Section: Dual Role Of Autophagy In Ichmentioning

confidence: 99%

Autophagy regulates inflammation in intracerebral hemorrhage: Enemy or friend?

Lenahan³

et al. 2023

Front. Cell. Neurosci.

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Intracerebral hemorrhage (ICH) is the second-largest stroke subtype and has a high mortality and disability rate. Secondary brain injury (SBI) is delayed after ICH. The main contributors to SBI are inflammation, oxidative stress, and excitotoxicity. Harmful substances from blood and hemolysis, such as hemoglobin, thrombin, and iron, induce SBI. When cells suffer stress, a critical protective mechanism called “autophagy” help to maintain the homeostasis of damaged cells, remove harmful substances or damaged organelles, and recycle them. Autophagy plays a critical role in the pathology of ICH, and its function remains controversial. Several lines of evidence demonstrate a pro-survival role for autophagy in ICH by facilitating the removal of damaged proteins and organelles. However, many studies have found that heme and iron can aggravate SBI by enhancing autophagy. Autophagy and inflammation are essential culprits in the progression of brain injury. It is a fascinating hypothesis that autophagy regulates inflammation in ICH-induced SBI. Autophagy could degrade and clear pro-IL-1β and apoptosis-associated speck-like protein containing a CARD (ASC) to antagonize NLRP3-mediated inflammation. In addition, mitophagy can remove endogenous activators of inflammasomes, such as reactive oxygen species (ROS), inflammatory components, and cytokines, in damaged mitochondria. However, many studies support the idea that autophagy activates microglia and aggravates microglial inflammation via the toll-like receptor 4 (TLR4) pathway. In addition, autophagy can promote ICH-induced SBI through inflammasome-dependent NLRP6-mediated inflammation. Moreover, some resident cells in the brain are involved in autophagy in regulating inflammation after ICH. Some compounds or therapeutic targets that regulate inflammation by autophagy may represent promising candidates for the treatment of ICH-induced SBI. In conclusion, the mutual regulation of autophagy and inflammation in ICH is worth exploring. The control of inflammation by autophagy will hopefully prove to be an essential treatment target for ICH.

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“…In addition to the time factor, the protein type of autophagy also impacts the pathological process of stroke. Studies have shown that STING can activate the autophagy of ferritin in the early stage of ischemic stroke and aggravate post‐stroke brain damage (Li et al, 2022). STING reaches a high level 3 days after ischemic stroke and is maintained until 7 days after ischemic stroke (Kong et al, 2022).…”

Section: Dna Sensing In Ischemic Strokementioning

confidence: 99%

DNA sensing in the pathological process of ischemic stroke

Zhang

Liao

2023

Eur J of Neuroscience

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The innate immune response plays an important role in the pathological process of ischemic stroke. Increasing evidence suggests that the inflammatory response triggered by the innate immune system hinders neurological and behavioural recovery after stroke. The perception of abnormal DNA and its downstream effects are an essential part of the innate immune system. The abnormal DNA is the major inducing factor for innate immune response and is sensed by a series of DNA sensors. In this review, we discussed the multiple roles of DNA sensing in the pathological process of ischemic stroke, with a special focus on DNA sensors Toll‐like receptor 9 (TLR9), absent in melanoma 2 (AIM2) and cyclic GMP‐AMP synthase (cGAS).

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cGAS-STING pathway aggravates early cerebral ischemia-reperfusion injury in mice by activating NCOA4-mediated ferritinophagy

Cited by 28 publications

References 51 publications

Role of microglia in stroke

Role of microglia in stroke

Autophagy regulates inflammation in intracerebral hemorrhage: Enemy or friend?

DNA sensing in the pathological process of ischemic stroke

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