Thioredoxin-interacting protein links endoplasmic reticulum stress to inflammatory brain injury and apoptosis after subarachnoid haemorrhage
Abstract Background Early brain injury (EBI) is considered a major contributor to the high morbidity and mortality associated with subarachnoid haemorrhage (SAH). Both of sterile inflammation and apoptosis are considered the important causes of EBI. Recently, it was confirmed that thioredoxin-intera...
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| Format: | Article |
| Language: | English |
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BMC
2017-05-01
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| Series: | Journal of Neuroinflammation |
| Subjects: | |
| Online Access: | http://link.springer.com/article/10.1186/s12974-017-0878-6 |
| _version_ | 1819017031374077952 |
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| author | Qing Zhao Xudong Che Hongxia Zhang Pianpian Fan Guanping Tan Liu Liu Dengzhi Jiang Jun Zhao Xiang Xiang Yidan Liang Xiaochuan Sun Zhaohui He |
| author_facet | Qing Zhao Xudong Che Hongxia Zhang Pianpian Fan Guanping Tan Liu Liu Dengzhi Jiang Jun Zhao Xiang Xiang Yidan Liang Xiaochuan Sun Zhaohui He |
| author_sort | Qing Zhao |
| collection | DOAJ |
| description | Abstract Background Early brain injury (EBI) is considered a major contributor to the high morbidity and mortality associated with subarachnoid haemorrhage (SAH). Both of sterile inflammation and apoptosis are considered the important causes of EBI. Recently, it was confirmed that thioredoxin-interacting protein (TXNIP) not only participates in inflammatory amplification but also stimulates the apoptosis signalling cascade pathway. However, whether the effects of TXNIP influence the pathogenesis of SAH remains unclear. Here, we hypothesize that TXNIP activity induced by endoplasmic reticulum stress (ER stress) may contribute to the pathogenesis of EBI through pro-inflammatory and pro-apoptotic mechanisms. Methods A total of 299 male Sprague–Dawley rats were used to create SAH models. Resveratrol (RES, 60 mg/kg) and two TXNIP small interfering RNA (siRNA) were used to inhibit TXNIP expression. The specific inhibitors of ER stress sensors were used to disrupt the link between TXNIP and ER stress. SAH grade, neurological deficits, brain water content and blood–brain barrier (BBB) permeability were evaluated simultaneously as prognostic indicators. Fluorescent double-labelling was employed to detect the location of TXNIP in cerebral cells. Western blot and TUNEL were performed to study the mechanisms of TXNIP and EBI. Results We found that TXNIP expression significantly increased after SAH, peaking at 48 h (0.48 ± 0.04, up to 3.2-fold) and decreasing at 72 h after surgery. This process was accompanied by the generation of inflammation-associated factors. TXNIP was expressed in the cytoplasm of neurons and was widely co-localized with TUNEL-positive cells in both the hippocampus and the cortex of SAH rats. We discovered for the first time that TXNIP was co-localized in neural immunocytes (microglia and astrocytes). After administration of RES, TXNIP siRNA and ER stress inhibitors, TXNIP expression was significantly reduced and the crosstalk between TXNIP and ER stress was disrupted; this was accompanied by a reduction in inflammatory and apoptotic factors, as well as attenuation of the prognostic indices. Conclusions These results may represent the critical evidence to support the pro-inflammatory and pro-apoptotic effects of TXNIP after SAH. Our data suggest that TXNIP participates in EBI after SAH by mediating inflammation and apoptosis; these pathways may represent a potential therapeutic strategy for SAH treatment. |
| first_indexed | 2024-12-21T02:57:03Z |
| format | Article |
| id | doaj.art-5bdc33ff1c694c71a59728b714c0d039 |
| institution | Directory Open Access Journal |
| issn | 1742-2094 |
| language | English |
| last_indexed | 2024-12-21T02:57:03Z |
| publishDate | 2017-05-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Neuroinflammation |
| spelling | doaj.art-5bdc33ff1c694c71a59728b714c0d0392022-12-21T19:18:18ZengBMCJournal of Neuroinflammation1742-20942017-05-0114111510.1186/s12974-017-0878-6Thioredoxin-interacting protein links endoplasmic reticulum stress to inflammatory brain injury and apoptosis after subarachnoid haemorrhageQing Zhao0Xudong Che1Hongxia Zhang2Pianpian Fan3Guanping Tan4Liu Liu5Dengzhi Jiang6Jun Zhao7Xiang Xiang8Yidan Liang9Xiaochuan Sun10Zhaohui He11Department of Neurosurgery, the First Affiliated Hospital of Chongqing Medical UniversityDepartment of Neurosurgery, the First Affiliated Hospital of Chongqing Medical UniversityDepartment of Neurosurgery, the First Affiliated Hospital of Chongqing Medical UniversityDepartment of Endocrinology, West China Hospital of Sichuan UniversityDepartment of Neurosurgery, the First Affiliated Hospital of Chongqing Medical UniversityDepartment of Neurosurgery, the First Affiliated Hospital of Chongqing Medical UniversityDepartment of Neurosurgery, the First Affiliated Hospital of Chongqing Medical UniversityDepartment of Neurosurgery, the First Affiliated Hospital of Chongqing Medical UniversityDepartment of Neurosurgery, the First Affiliated Hospital of Chongqing Medical UniversityDepartment of Neurosurgery, the First Affiliated Hospital of Chongqing Medical UniversityDepartment of Neurosurgery, the First Affiliated Hospital of Chongqing Medical UniversityDepartment of Neurosurgery, the First Affiliated Hospital of Chongqing Medical UniversityAbstract Background Early brain injury (EBI) is considered a major contributor to the high morbidity and mortality associated with subarachnoid haemorrhage (SAH). Both of sterile inflammation and apoptosis are considered the important causes of EBI. Recently, it was confirmed that thioredoxin-interacting protein (TXNIP) not only participates in inflammatory amplification but also stimulates the apoptosis signalling cascade pathway. However, whether the effects of TXNIP influence the pathogenesis of SAH remains unclear. Here, we hypothesize that TXNIP activity induced by endoplasmic reticulum stress (ER stress) may contribute to the pathogenesis of EBI through pro-inflammatory and pro-apoptotic mechanisms. Methods A total of 299 male Sprague–Dawley rats were used to create SAH models. Resveratrol (RES, 60 mg/kg) and two TXNIP small interfering RNA (siRNA) were used to inhibit TXNIP expression. The specific inhibitors of ER stress sensors were used to disrupt the link between TXNIP and ER stress. SAH grade, neurological deficits, brain water content and blood–brain barrier (BBB) permeability were evaluated simultaneously as prognostic indicators. Fluorescent double-labelling was employed to detect the location of TXNIP in cerebral cells. Western blot and TUNEL were performed to study the mechanisms of TXNIP and EBI. Results We found that TXNIP expression significantly increased after SAH, peaking at 48 h (0.48 ± 0.04, up to 3.2-fold) and decreasing at 72 h after surgery. This process was accompanied by the generation of inflammation-associated factors. TXNIP was expressed in the cytoplasm of neurons and was widely co-localized with TUNEL-positive cells in both the hippocampus and the cortex of SAH rats. We discovered for the first time that TXNIP was co-localized in neural immunocytes (microglia and astrocytes). After administration of RES, TXNIP siRNA and ER stress inhibitors, TXNIP expression was significantly reduced and the crosstalk between TXNIP and ER stress was disrupted; this was accompanied by a reduction in inflammatory and apoptotic factors, as well as attenuation of the prognostic indices. Conclusions These results may represent the critical evidence to support the pro-inflammatory and pro-apoptotic effects of TXNIP after SAH. Our data suggest that TXNIP participates in EBI after SAH by mediating inflammation and apoptosis; these pathways may represent a potential therapeutic strategy for SAH treatment.http://link.springer.com/article/10.1186/s12974-017-0878-6Subarachnoid haemorrhageEarly brain injury (EBI)InflammationApoptosisThioredoxin-interacting proteinEndoplasmic reticulum stress |
| spellingShingle | Qing Zhao Xudong Che Hongxia Zhang Pianpian Fan Guanping Tan Liu Liu Dengzhi Jiang Jun Zhao Xiang Xiang Yidan Liang Xiaochuan Sun Zhaohui He Thioredoxin-interacting protein links endoplasmic reticulum stress to inflammatory brain injury and apoptosis after subarachnoid haemorrhage Journal of Neuroinflammation Subarachnoid haemorrhage Early brain injury (EBI) Inflammation Apoptosis Thioredoxin-interacting protein Endoplasmic reticulum stress |
| title | Thioredoxin-interacting protein links endoplasmic reticulum stress to inflammatory brain injury and apoptosis after subarachnoid haemorrhage |
| title_full | Thioredoxin-interacting protein links endoplasmic reticulum stress to inflammatory brain injury and apoptosis after subarachnoid haemorrhage |
| title_fullStr | Thioredoxin-interacting protein links endoplasmic reticulum stress to inflammatory brain injury and apoptosis after subarachnoid haemorrhage |
| title_full_unstemmed | Thioredoxin-interacting protein links endoplasmic reticulum stress to inflammatory brain injury and apoptosis after subarachnoid haemorrhage |
| title_short | Thioredoxin-interacting protein links endoplasmic reticulum stress to inflammatory brain injury and apoptosis after subarachnoid haemorrhage |
| title_sort | thioredoxin interacting protein links endoplasmic reticulum stress to inflammatory brain injury and apoptosis after subarachnoid haemorrhage |
| topic | Subarachnoid haemorrhage Early brain injury (EBI) Inflammation Apoptosis Thioredoxin-interacting protein Endoplasmic reticulum stress |
| url | http://link.springer.com/article/10.1186/s12974-017-0878-6 |
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