Vagus nerve stimulation inhibits pyroptosis and improves outcome of cerebral ischemic stroke by upregulating osteopontin (SPP1) to disturb ASC oligomerization
Abstract Background Vagus nerve stimulation (VNS) brings new hope for handling stroke. Our previous study confirmed that VNS could reduce neuronal pyroptosis and improve stroke prognosis. However, how VNS suppresses pyroptosis remains poorly understood. Osteopontin (OPN,SPP1) plays a neuroprotective...
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2025-07-01
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| Online Access: | https://doi.org/10.1186/s12916-025-04242-4 |
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| author | Jun Wen Hao Tang Ling Wang Qinghuan Yang Yong Zhao Yu Ren Ting Qin Xuemei Li Jianfeng Xu Gongwei Jia Qin Yang |
| author_facet | Jun Wen Hao Tang Ling Wang Qinghuan Yang Yong Zhao Yu Ren Ting Qin Xuemei Li Jianfeng Xu Gongwei Jia Qin Yang |
| author_sort | Jun Wen |
| collection | DOAJ |
| description | Abstract Background Vagus nerve stimulation (VNS) brings new hope for handling stroke. Our previous study confirmed that VNS could reduce neuronal pyroptosis and improve stroke prognosis. However, how VNS suppresses pyroptosis remains poorly understood. Osteopontin (OPN,SPP1) plays a neuroprotective role. Therefore, this study aims to determine whether vagus nerve stimulation (VNS) inhibits pyroptosis and promotes recovery from cerebral ischemic injury through osteopontin (OPN), and to elucidate the mechanisms by which OPN regulates pyroptosis. Methods Acute ischemic stroke (AIS) patients and healthy controls were recruited. The middle cerebral artery ischemia–reperfusion (MCAO/R) model of rats in vivo, the oxygen–glucose deprivation and reperfusion (OGD/R) and lipopolysaccharide (LPS) + adenosine triphosphate (ATP) models of microglia in vitro were established. Gene analysis of GEO public dataset (GSE61616), analysis of proteomics, western blotting, Co-immunoprecipitation (Co-IP) analysis, immunofluorescence staining, ELISA, TTC staining, TUNEL staining, transmission electron microscopy (TEM), scanning electron microscopy (SEM) and neurological function score were used to examinate expressions or concentrations of osteopontin, pyroptosis-related molecules, OPN-ASC interaction, infarct volume, neurological function, cell membrane pore, respectively. Results In MCAO/R rats and AIS patients, osteopontin levels were elevated. Intranasally administered recombinant osteopontin (rOPN) and VNS reduced pyroptosis and improved neurological deficits. VNS upregulated osteopontin expression in MCAO/R rats and AIS patients. Small interfering OPN RNA (siOPN) reversed effects of VNS on pyroptosis and outcome of MCAO/R injury in rats. The binding energy of OPN and ASC was -11.7 kcal/mol. LPS + ATP enhanced OPN-ASC interaction, and rOPN interfered with ASC oligomerization. Conditioned medium of microglia treated with rOPN reversed LPS + ATP-induced neruonal injury. Collectively, OPN may serve as a potential mediator through which VNS inhibits pyroptosis and improves the outcome of ischemic stroke, thereby representing a promising therapeutic target for stroke treatment. Conclusions These findings suggest that VNS alleviates pyroptosis and improves the outcome of cerebral ischemic stroke by upregulating osteopontin (OPN), which interferes with ASC oligomerization. Graphical Abstract |
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| institution | Kabale University |
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| publishDate | 2025-07-01 |
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| spelling | doaj-art-439a2843a3fb4d03a2b9de59d1ca77a32025-08-20T03:42:53ZengBMCBMC Medicine1741-70152025-07-0123112110.1186/s12916-025-04242-4Vagus nerve stimulation inhibits pyroptosis and improves outcome of cerebral ischemic stroke by upregulating osteopontin (SPP1) to disturb ASC oligomerizationJun Wen0Hao Tang1Ling Wang2Qinghuan Yang3Yong Zhao4Yu Ren5Ting Qin6Xuemei Li7Jianfeng Xu8Gongwei Jia9Qin Yang10Department of Neurology, The Frist Affiliated Hospital of Chongqing Medical University, Yuzhong DistrictDepartment of Neurology, The Frist Affiliated Hospital of Chongqing Medical University, Yuzhong DistrictDepartment of Neurology, The Frist Affiliated Hospital of Chongqing Medical University, Yuzhong DistrictDepartment of Neurology, The Frist Affiliated Hospital of Chongqing Medical University, Yuzhong DistrictDepartment of Neurology, The Frist Affiliated Hospital of Chongqing Medical University, Yuzhong DistrictDepartment of Neurology, The Frist Affiliated Hospital of Chongqing Medical University, Yuzhong DistrictDepartment of Respiratory Disease, Daping Hospital, Army Medical UniversityDepartment of Neurology, The Second People’s Hospital of Chongqing Banan DistrictDepartment of Neurosurgery, The Third People’s Hospital of MianyangDepartment of Rehabilitation, The Second Affiliated Hospital of Chongqing Medical UniversityDepartment of Neurology, The Frist Affiliated Hospital of Chongqing Medical University, Yuzhong DistrictAbstract Background Vagus nerve stimulation (VNS) brings new hope for handling stroke. Our previous study confirmed that VNS could reduce neuronal pyroptosis and improve stroke prognosis. However, how VNS suppresses pyroptosis remains poorly understood. Osteopontin (OPN,SPP1) plays a neuroprotective role. Therefore, this study aims to determine whether vagus nerve stimulation (VNS) inhibits pyroptosis and promotes recovery from cerebral ischemic injury through osteopontin (OPN), and to elucidate the mechanisms by which OPN regulates pyroptosis. Methods Acute ischemic stroke (AIS) patients and healthy controls were recruited. The middle cerebral artery ischemia–reperfusion (MCAO/R) model of rats in vivo, the oxygen–glucose deprivation and reperfusion (OGD/R) and lipopolysaccharide (LPS) + adenosine triphosphate (ATP) models of microglia in vitro were established. Gene analysis of GEO public dataset (GSE61616), analysis of proteomics, western blotting, Co-immunoprecipitation (Co-IP) analysis, immunofluorescence staining, ELISA, TTC staining, TUNEL staining, transmission electron microscopy (TEM), scanning electron microscopy (SEM) and neurological function score were used to examinate expressions or concentrations of osteopontin, pyroptosis-related molecules, OPN-ASC interaction, infarct volume, neurological function, cell membrane pore, respectively. Results In MCAO/R rats and AIS patients, osteopontin levels were elevated. Intranasally administered recombinant osteopontin (rOPN) and VNS reduced pyroptosis and improved neurological deficits. VNS upregulated osteopontin expression in MCAO/R rats and AIS patients. Small interfering OPN RNA (siOPN) reversed effects of VNS on pyroptosis and outcome of MCAO/R injury in rats. The binding energy of OPN and ASC was -11.7 kcal/mol. LPS + ATP enhanced OPN-ASC interaction, and rOPN interfered with ASC oligomerization. Conditioned medium of microglia treated with rOPN reversed LPS + ATP-induced neruonal injury. Collectively, OPN may serve as a potential mediator through which VNS inhibits pyroptosis and improves the outcome of ischemic stroke, thereby representing a promising therapeutic target for stroke treatment. Conclusions These findings suggest that VNS alleviates pyroptosis and improves the outcome of cerebral ischemic stroke by upregulating osteopontin (OPN), which interferes with ASC oligomerization. Graphical Abstracthttps://doi.org/10.1186/s12916-025-04242-4Ischemic strokeVagus nerve stimulationOsteopontinPyroptosisASC |
| spellingShingle | Jun Wen Hao Tang Ling Wang Qinghuan Yang Yong Zhao Yu Ren Ting Qin Xuemei Li Jianfeng Xu Gongwei Jia Qin Yang Vagus nerve stimulation inhibits pyroptosis and improves outcome of cerebral ischemic stroke by upregulating osteopontin (SPP1) to disturb ASC oligomerization BMC Medicine Ischemic stroke Vagus nerve stimulation Osteopontin Pyroptosis ASC |
| title | Vagus nerve stimulation inhibits pyroptosis and improves outcome of cerebral ischemic stroke by upregulating osteopontin (SPP1) to disturb ASC oligomerization |
| title_full | Vagus nerve stimulation inhibits pyroptosis and improves outcome of cerebral ischemic stroke by upregulating osteopontin (SPP1) to disturb ASC oligomerization |
| title_fullStr | Vagus nerve stimulation inhibits pyroptosis and improves outcome of cerebral ischemic stroke by upregulating osteopontin (SPP1) to disturb ASC oligomerization |
| title_full_unstemmed | Vagus nerve stimulation inhibits pyroptosis and improves outcome of cerebral ischemic stroke by upregulating osteopontin (SPP1) to disturb ASC oligomerization |
| title_short | Vagus nerve stimulation inhibits pyroptosis and improves outcome of cerebral ischemic stroke by upregulating osteopontin (SPP1) to disturb ASC oligomerization |
| title_sort | vagus nerve stimulation inhibits pyroptosis and improves outcome of cerebral ischemic stroke by upregulating osteopontin spp1 to disturb asc oligomerization |
| topic | Ischemic stroke Vagus nerve stimulation Osteopontin Pyroptosis ASC |
| url | https://doi.org/10.1186/s12916-025-04242-4 |
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