ROS-regulated SUR1-TRPM4 drives persistent activation of NLRP3 inflammasome in microglia after whole-brain radiation
Abstract Delayed radiation-induced brain injury (RIBI) characterized by progressive cognitive decline significantly impacts patient outcomes after radiotherapy. The activation of NLRP3 inflammasome within microglia after brain radiation is involved in the progression of RIBI by mediating inflammator...
Saved in:
| Main Authors: | , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
BMC
2025-01-01
|
| Series: | Acta Neuropathologica Communications |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s40478-025-01932-1 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1832571186275418112 |
|---|---|
| author | Yuan Chang Yihua He Di Wang Kunxue Zhang Yuzhen Zhang Zhentong Li Shuxin Zeng Sheng Xiao Suyue Pan Kaibin Huang |
| author_facet | Yuan Chang Yihua He Di Wang Kunxue Zhang Yuzhen Zhang Zhentong Li Shuxin Zeng Sheng Xiao Suyue Pan Kaibin Huang |
| author_sort | Yuan Chang |
| collection | DOAJ |
| description | Abstract Delayed radiation-induced brain injury (RIBI) characterized by progressive cognitive decline significantly impacts patient outcomes after radiotherapy. The activation of NLRP3 inflammasome within microglia after brain radiation is involved in the progression of RIBI by mediating inflammatory responses. We have previously shown that sulfonylurea receptor 1-transient receptor potential M4 (SUR1-TRPM4) mediates microglial NLRP3-related inflammation following global brain ischemia. However, the role of SUR1-TRPM4 in RIBI remains unclear. Here, we found that whole-brain radiation induced up-regulation and assembly of SUR1-TRPM4, which further activated the NLRP3 inflammasome in microglia and caused persistent neuroinflammation in mice. Blocking SUR1-TRPM4 by glibenclamide or gene deletion of Trpm4 effectively prevented NLRP3-mediated neuroinflammation and alleviated RIBI. Utilizing the mouse model of RIBI and irradiated BV2 cells, we further demonstrated that irradiation caused mitochondrial damage to microglia, leading to violent release of reactive oxygen species (ROS), which enhanced the transcription of SUR1, TRPM4, and NLRP3 inflammasome-related molecules. Moreover, ROS up-regulated ten-eleven translocation 2 (TET2) to enhance TRPM4 expression by mediating the demethylation of the gene promoter, thereby facilitating the assembly of SUR1-TRPM4 in microglia. In summary, this study deciphers that SUR1-TRPM4 crucially mediates the persistent activation of microglial NLRP3 inflammasome under the action of ROS after whole-brain radiation, offering novel therapeutic strategies for delayed RIBI as well as other NLRP3-related neurological disorders involving excessive ROS production. |
| format | Article |
| id | doaj-art-9cdc2ecb7ce64c1aa2a8864122dcf6a8 |
| institution | Kabale University |
| issn | 2051-5960 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | BMC |
| record_format | Article |
| series | Acta Neuropathologica Communications |
| spelling | doaj-art-9cdc2ecb7ce64c1aa2a8864122dcf6a82025-02-02T12:47:06ZengBMCActa Neuropathologica Communications2051-59602025-01-0113112610.1186/s40478-025-01932-1ROS-regulated SUR1-TRPM4 drives persistent activation of NLRP3 inflammasome in microglia after whole-brain radiationYuan Chang0Yihua He1Di Wang2Kunxue Zhang3Yuzhen Zhang4Zhentong Li5Shuxin Zeng6Sheng Xiao7Suyue Pan8Kaibin Huang9Department of Neurology, Nanfang Hospital, Southern Medical UniversityDepartment of Neurology, Nanfang Hospital, Southern Medical UniversityDermatology Hospital, Southern Medical UniversityDepartment of Neurology, Nanfang Hospital, Southern Medical UniversityDepartment of Neurology, Nanfang Hospital, Southern Medical UniversityDepartment of Neurology, Nanfang Hospital, Southern Medical UniversityDepartment of Neurology, Nanfang Hospital, Southern Medical UniversityDepartment of Neurology, Nanfang Hospital, Southern Medical UniversityDepartment of Neurology, Nanfang Hospital, Southern Medical UniversityDepartment of Neurology, Nanfang Hospital, Southern Medical UniversityAbstract Delayed radiation-induced brain injury (RIBI) characterized by progressive cognitive decline significantly impacts patient outcomes after radiotherapy. The activation of NLRP3 inflammasome within microglia after brain radiation is involved in the progression of RIBI by mediating inflammatory responses. We have previously shown that sulfonylurea receptor 1-transient receptor potential M4 (SUR1-TRPM4) mediates microglial NLRP3-related inflammation following global brain ischemia. However, the role of SUR1-TRPM4 in RIBI remains unclear. Here, we found that whole-brain radiation induced up-regulation and assembly of SUR1-TRPM4, which further activated the NLRP3 inflammasome in microglia and caused persistent neuroinflammation in mice. Blocking SUR1-TRPM4 by glibenclamide or gene deletion of Trpm4 effectively prevented NLRP3-mediated neuroinflammation and alleviated RIBI. Utilizing the mouse model of RIBI and irradiated BV2 cells, we further demonstrated that irradiation caused mitochondrial damage to microglia, leading to violent release of reactive oxygen species (ROS), which enhanced the transcription of SUR1, TRPM4, and NLRP3 inflammasome-related molecules. Moreover, ROS up-regulated ten-eleven translocation 2 (TET2) to enhance TRPM4 expression by mediating the demethylation of the gene promoter, thereby facilitating the assembly of SUR1-TRPM4 in microglia. In summary, this study deciphers that SUR1-TRPM4 crucially mediates the persistent activation of microglial NLRP3 inflammasome under the action of ROS after whole-brain radiation, offering novel therapeutic strategies for delayed RIBI as well as other NLRP3-related neurological disorders involving excessive ROS production.https://doi.org/10.1186/s40478-025-01932-1Radiation-induced brain injuryMicrogliaNLRP3 inflammasomeSUR1-TRPM4ROSTET2 |
| spellingShingle | Yuan Chang Yihua He Di Wang Kunxue Zhang Yuzhen Zhang Zhentong Li Shuxin Zeng Sheng Xiao Suyue Pan Kaibin Huang ROS-regulated SUR1-TRPM4 drives persistent activation of NLRP3 inflammasome in microglia after whole-brain radiation Acta Neuropathologica Communications Radiation-induced brain injury Microglia NLRP3 inflammasome SUR1-TRPM4 ROS TET2 |
| title | ROS-regulated SUR1-TRPM4 drives persistent activation of NLRP3 inflammasome in microglia after whole-brain radiation |
| title_full | ROS-regulated SUR1-TRPM4 drives persistent activation of NLRP3 inflammasome in microglia after whole-brain radiation |
| title_fullStr | ROS-regulated SUR1-TRPM4 drives persistent activation of NLRP3 inflammasome in microglia after whole-brain radiation |
| title_full_unstemmed | ROS-regulated SUR1-TRPM4 drives persistent activation of NLRP3 inflammasome in microglia after whole-brain radiation |
| title_short | ROS-regulated SUR1-TRPM4 drives persistent activation of NLRP3 inflammasome in microglia after whole-brain radiation |
| title_sort | ros regulated sur1 trpm4 drives persistent activation of nlrp3 inflammasome in microglia after whole brain radiation |
| topic | Radiation-induced brain injury Microglia NLRP3 inflammasome SUR1-TRPM4 ROS TET2 |
| url | https://doi.org/10.1186/s40478-025-01932-1 |
| work_keys_str_mv | AT yuanchang rosregulatedsur1trpm4drivespersistentactivationofnlrp3inflammasomeinmicrogliaafterwholebrainradiation AT yihuahe rosregulatedsur1trpm4drivespersistentactivationofnlrp3inflammasomeinmicrogliaafterwholebrainradiation AT diwang rosregulatedsur1trpm4drivespersistentactivationofnlrp3inflammasomeinmicrogliaafterwholebrainradiation AT kunxuezhang rosregulatedsur1trpm4drivespersistentactivationofnlrp3inflammasomeinmicrogliaafterwholebrainradiation AT yuzhenzhang rosregulatedsur1trpm4drivespersistentactivationofnlrp3inflammasomeinmicrogliaafterwholebrainradiation AT zhentongli rosregulatedsur1trpm4drivespersistentactivationofnlrp3inflammasomeinmicrogliaafterwholebrainradiation AT shuxinzeng rosregulatedsur1trpm4drivespersistentactivationofnlrp3inflammasomeinmicrogliaafterwholebrainradiation AT shengxiao rosregulatedsur1trpm4drivespersistentactivationofnlrp3inflammasomeinmicrogliaafterwholebrainradiation AT suyuepan rosregulatedsur1trpm4drivespersistentactivationofnlrp3inflammasomeinmicrogliaafterwholebrainradiation AT kaibinhuang rosregulatedsur1trpm4drivespersistentactivationofnlrp3inflammasomeinmicrogliaafterwholebrainradiation |