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Brain-cervical lymph node crosstalk contributes to brain injury-induced by subarachnoid hemorrhage in mice

ABSTRACT: The neuroinflammation and peripheral immune response following subarachnoid hemorrhage (SAH) aggravates early brain injury and lead to poor prognosis. Cross-talk between brain and cervical lymph nodes (CLNs) plays a crucial role in neuroinflammation and neurological diseases-associated brain injury. However, whether CLNs participate in brain damage and how injured brain activates immune system in SAH remain unclear. Previously, we reported that extravasated erythrocytes are drained into CLNs early following SAH. Here, we demonstrated that the removal of CLNs attenuated neuroinflammation and neurological deficits in 2 mouse models of SAH. Interestingly, we found that extravasated erythrocytes in CLNs following SAH were significantly engulfed by LYVE-1+ lymphatic endothelial cells (LECs) in both mandibular and deep CLNs. Single-cell RNA sequencing of mandibular LNs revealed that the medullary LEC is the primary LEC subset to degrade erythrocytes via lysosome protease cathepsin S. LECs treated by erythrocytes in vitro leaded to increasing the expression of genes related to inflammatory response, chemokines and lysosome protease cathepsin S. Importantly, deficiency of cathepsin S specifically in LECs using transgenic mice or blockage of cathepsin S by its inhibitor reduced SAH-induced brain damage. These results revealed a mechanism of how extravasated erythrocytes triggers a CLN-mediated inflammatory response and the aggravation of brain injury in SAH, and target this process may become effective therapeutic strategies to alleviate SAH pathology.

ORGANISM(S): Mus musculus

PROVIDER: GSE295771 | GEO | 2025/08/14

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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Brain-cervical lymph node crosstalk contributes to brain injury-induced by subarachnoid hemorrhage in mice

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