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Microglia aggravate white matter injury via C3/C3aR pathway after experimental subrachnoid hemorrhage

ABSTRACT: Activation of microglia induces neuroinflammation in acute and chronic phase is closely related to the white matter injury (WMI) pathophysiologyafter subrachnoid hemorrhage (SAH). The complement C3a receptor (C3aR) has a dual role in regulating inflammation and plays a role in neurodevelopment, neuroplasticity and neurodegeneration, but it’s effect on WMI during SAH re'mairemains unknown. In this study, 175 male C57BL/6J mice received SAH by endovascular perforation. oxy-Hb was used to simulate SAH in vitro. Multiple technical approaches, including immunohistochemistry, transcriptome sequencing, neurological function assessment, and various molecular biotechnologies, were used to assess the activation of the C3-C3aR pathway after SAH and its effects on microglial polarizations and WMI after SAH. The results showed that abnormal microglial activation after SAH was accompanied by upregulation of complement C3 and C3aR. C3aR inhibition reduced abnormal microglial activation, attenuated neuroinflammation, ameliorated WMI and cognitive deficits after SAH. RNA-Seq revealed that C3aR inhibition downregulated several immune and inflammatory pathways and ameliorated cellular injury by downregulating Pidd1 expression. The adverse effects of C3-C3aR in SAH may be related to Endoplasmic reticulum (ER) stress-dependent cellular injury and formation of inflammasome. PERK agonists exacerbate cellular injury and neuroinflammation attenuated by C3aR inhibition. Intranasal C3a treatment during the subacute phase of SAH helps to reduce astrocyte reactivity and ameliorate cognitive deficits after SAH. In conclusion, these findings suggest that C3aR plays a critical role in the regulation of neuroinflammation and WMI after SAH, providing new therapeutic targets to ameliorate WMI and cognitive deficits after SAH.

ORGANISM(S): Mus musculus

PROVIDER: GSE254320 | GEO | 2025/01/25

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 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>.

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>.

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Microglia aggravate white matter injury via C3/C3aR pathway after experimental subrachnoid hemorrhage

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