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Deletion of Bak1 alleviates microglial necroptosis and neuroinflammation after experimental subarachnoid hemorrhage

ABSTRACT: Microglial necroptosis exacerbates neurodegenerative diseases, central nervous system injury and demonstrates a pro-inflammatory process, but its contribution to subarachnoid hemorrhage (SAH) is poorly characterized. BCL-2 homologous antagonist-killer protein (Bak1), a critical regulatory molecule of endogenous apoptosis, can be involved in the pathological process of necroptosis by regulating mitochondrial permeability. In this study, we revealed microglia undergo necroptosis after subarachnoid hemorrhage in vivo and vitro. We found that Bak1 was elevated at 24h after SAH. Knocked-down of Bak1 by adeno-associated virus attenuates microglial necroptosis, alleviates neuroinflammation, and improves neurological function after SAH. To further explore the corresponding mechanisms, oxyhemoglobin induces necroptosis in BV2 microglia, increasing Bak1 expression and mediating pro-inflammatory phenotype transformation, exacerbating oxidative stress and neuroinflammation. Abrogating BV2 Bak1 reduces necroptosis by downregulating the expression of phosphorylated pseudokinase mixed lineage kinase domain-like protein (p-MLKL), then downregulates pro-inflammatory phenotype gene expression. RNA-Seq shows that disrupting BV2 Bak1 downregulates multiple immune and inflammatory pathways and ameliorates cell injury by elevating Thrombospondin 1 (THBS1) expression. In summary, we identified a critical regulatory role for Bak1 in microglial necroptosis and neuroinflammation after SAH. Bak1 is expected to be a new therapeutic target, and it provides a new idea for the treatment strategy of SAH.

ORGANISM(S): Mus musculus

PROVIDER: GSE200224 | GEO | 2022/04/10

REPOSITORIES: GEO

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Project description:BACKGROUND: Subarachnoid hemorrhage (SAH) is a devastating cerebrovascular disease with a poor prognosis. Accumulating studies have reported that gut microbiota contributes to the pathophysiology of several central nervous system diseases. However, whether SAH can change gut microbiota composition and affected gut microbiota is involved in the development of secondary brain injury following SAH remains unclear.METHODS: A retrospective case-control study was performed in unruptured intracranial aneurysm (UIA, CTL) and ruptured intracranial aneurysm (SAH) patients. Patients' fecal and serum samples were collected and sequenced by metagenome and metabolome. The experimental SAH mice models were established, and their feces and serum were also analyzed by 16S rRNA and metabolic sequencing. Fecal microbiota from SAH patients and mice was transplanted to ABX mice to investigate the relationship between the gut microbiota and secondary brain injury following SAH.RESULTS: SAH seriously influenced gut microbiota composition and significantly increased the relative abundance of the genus Escherichia. SAH also considerably reduced the production of gut microbiota-derived butyric acid. Furthermore, SAH-induced gut microbiota dysbiosis aggravated brain injury and cognitive deficits in ABX mice by promoting inflammatory response. Sodium butyrate (NaB) administration protected against secondary brain injury following SAH by inhibiting pyroptosis-related neuroinflammation, which is mediated by NLRP1/Caspase-1/GSDMD and Caspase-3/GSDME signaling pathways. NaB drinking pretreatment also alleviated secondary brain injury following SAH by increasing the relative abundance of butyric acid-producing bacteria, such as Dubosiella and Faecalibaculum, and decreasing the Escherichia abundance.CONCLUSION: SAH contributed to gut microbiota dysbiosis and changed gut microbiota exacerbated secondary brain injury after SAH. Supplement with gut microbiota-derived butyric acid protected against brain injury following SAH by inhibiting NLRP1/Caspase-1/GSDMD and Caspase-3/GSDME-mediated neuronal pyroptosis. Linked studies:UPLC-MS/MS assays of murine samples are reported in this study.UPLC-MS/MS assays of human samples are reported in <a href='https://www.ebi.ac.uk/metabolights/MTBLS9087' rel='noopener noreferrer' target='_blank'>MTBLS9087</a>.

Project description:BACKGROUND: Subarachnoid hemorrhage (SAH) is a devastating cerebrovascular disease with a poor prognosis. Accumulating studies have reported that gut microbiota contributes to the pathophysiology of several central nervous system diseases. However, whether SAH can change gut microbiota composition and affected gut microbiota is involved in the development of secondary brain injury following SAH remains unclear.METHODS: A retrospective case-control study was performed in unruptured intracranial aneurysm (UIA, CTL) and ruptured intracranial aneurysm (SAH) patients. Patients' fecal and serum samples were collected and sequenced by metagenome and metabolome. The experimental SAH mice models were established, and their feces and serum were also analyzed by 16S rRNA and metabolic sequencing. Fecal microbiota from SAH patients and mice was transplanted to ABX mice to investigate the relationship between the gut microbiota and secondary brain injury following SAH.RESULTS: SAH seriously influenced gut microbiota composition and significantly increased the relative abundance of the genus Escherichia. SAH also considerably reduced the production of gut microbiota-derived butyric acid. Furthermore, SAH-induced gut microbiota dysbiosis aggravated brain injury and cognitive deficits in ABX mice by promoting inflammatory response. Sodium butyrate (NaB) administration protected against secondary brain injury following SAH by inhibiting pyroptosis-related neuroinflammation, which is mediated by NLRP1/Caspase-1/GSDMD and Caspase-3/GSDME signaling pathways. NaB drinking pretreatment also alleviated secondary brain injury following SAH by increasing the relative abundance of butyric acid-producing bacteria, such as Dubosiella and Faecalibaculum, and decreasing the Escherichia abundance.CONCLUSION: SAH contributed to gut microbiota dysbiosis and changed gut microbiota exacerbated secondary brain injury after SAH. Supplement with gut microbiota-derived butyric acid protected against brain injury following SAH by inhibiting NLRP1/Caspase-1/GSDMD and Caspase-3/GSDME-mediated neuronal pyroptosis. Linked studies:UPLC-MS/MS assays of human samples are reported in this study.UPLC-MS/MS assays of  murine samples are reported in <a href='https://www.ebi.ac.uk/metabolights/MTBLS9100' rel='noopener noreferrer' target='_blank'>MTBLS9100</a>.

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Deletion of Bak1 alleviates microglial necroptosis and neuroinflammation after experimental subarachnoid hemorrhage

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