A20 negatively regulates necroptosis-induced microglia/macrophages polarization and mediates cerebral ischemic tolerance via inhibiting the ubiquitination of RIP3
Abstract Neuronal necroptosis appears to be suppressed by the deubiquitinating enzyme A20 and is capable to regulate the polarization of microglia/macrophages after cerebral ischemia. We have demonstrated that hypoxic preconditioning (HPC) can alleviate receptor interacting protein 3 (RIP3)-induced...
Saved in:
| Main Authors: | , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Nature Publishing Group
2024-12-01
|
| Series: | Cell Death and Disease |
| Online Access: | https://doi.org/10.1038/s41419-024-07293-2 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1846112101362302976 |
|---|---|
| author | Meiqian Qiu Wenhao Zhang Jiahua Dai Weiwen Sun Meijing Lai Shiyi Tang En Xu Yuping Ning Lixuan Zhan |
| author_facet | Meiqian Qiu Wenhao Zhang Jiahua Dai Weiwen Sun Meijing Lai Shiyi Tang En Xu Yuping Ning Lixuan Zhan |
| author_sort | Meiqian Qiu |
| collection | DOAJ |
| description | Abstract Neuronal necroptosis appears to be suppressed by the deubiquitinating enzyme A20 and is capable to regulate the polarization of microglia/macrophages after cerebral ischemia. We have demonstrated that hypoxic preconditioning (HPC) can alleviate receptor interacting protein 3 (RIP3)-induced necroptosis in CA1 after transient global cerebral ischemia (tGCI). However, it is still unclear whether HPC serves to regulate the phenotypic polarization of microglia/macrophages after cerebral ischemia by mitigating neuronal necroptosis. We hence aim to elucidate the underlying mechanism(s) by which the ubiquitination of RIP3-dependent necroptosis regulated by A20 affects microglia/macrophages phenotype after cerebral ischemic tolerance. We found that microglia/macrophages in CA1 of rats underwent M1 and M2 phenotypic polarization in response to tGCI. Notably, the treatment with HPC, as well as inhibitors of necroptosis, including Nec-1 and mixed lineage kinase domain-like (MLKL) siRNA, attenuated neuroinflammation associated with M1 polarization of microglia/macrophages induced by tGCI. Mechanistically, HPC was revealed to upregulate A20 and in turn enhance the interaction between A20 and RIP3, thereby reducing K63-linked polyubiquitination of RIP3 in CA1 after tGCI. Consequently, RIP3-dependent necroptosis and the M1 polarization of microglia/macrophages were blocked either by HPC or via overexpression of A20 in neurons, which ultimately mitigated cerebral injury in CA1 after tGCI. These data support that A20 serves as a crucial mediator of microglia/macrophages polarization by suppressing neuronal necroptosis in a RIP3 ubiquitination-dependent manner after tGCI. Also, a novel mechanism by which HPC functions in cerebral ischemic tolerance is elucidated. |
| format | Article |
| id | doaj-art-2d7ff083f41a4be6b4d65d0f04e6ec25 |
| institution | Kabale University |
| issn | 2041-4889 |
| language | English |
| publishDate | 2024-12-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death and Disease |
| spelling | doaj-art-2d7ff083f41a4be6b4d65d0f04e6ec252024-12-22T12:51:05ZengNature Publishing GroupCell Death and Disease2041-48892024-12-01151211510.1038/s41419-024-07293-2A20 negatively regulates necroptosis-induced microglia/macrophages polarization and mediates cerebral ischemic tolerance via inhibiting the ubiquitination of RIP3Meiqian Qiu0Wenhao Zhang1Jiahua Dai2Weiwen Sun3Meijing Lai4Shiyi Tang5En Xu6Yuping Ning7Lixuan Zhan8Department of Neurology, Institute of Neuroscience, Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province and the Ministry of Education of China, The Second Affiliated Hospital, Guangzhou Medical UniversityDepartment of Neurology, Institute of Neuroscience, Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province and the Ministry of Education of China, The Second Affiliated Hospital, Guangzhou Medical UniversityDepartment of Neurology, Institute of Neuroscience, Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province and the Ministry of Education of China, The Second Affiliated Hospital, Guangzhou Medical UniversityDepartment of Neurology, Institute of Neuroscience, Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province and the Ministry of Education of China, The Second Affiliated Hospital, Guangzhou Medical UniversityDepartment of Neurology, Institute of Neuroscience, Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province and the Ministry of Education of China, The Second Affiliated Hospital, Guangzhou Medical UniversityDepartment of Neurology, Institute of Neuroscience, Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province and the Ministry of Education of China, The Second Affiliated Hospital, Guangzhou Medical UniversityDepartment of Neurology, Institute of Neuroscience, Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province and the Ministry of Education of China, The Second Affiliated Hospital, Guangzhou Medical UniversityThe Affiliated Brain Hospital of Guangzhou Medical UniversityDepartment of Neurology, Institute of Neuroscience, Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province and the Ministry of Education of China, The Second Affiliated Hospital, Guangzhou Medical UniversityAbstract Neuronal necroptosis appears to be suppressed by the deubiquitinating enzyme A20 and is capable to regulate the polarization of microglia/macrophages after cerebral ischemia. We have demonstrated that hypoxic preconditioning (HPC) can alleviate receptor interacting protein 3 (RIP3)-induced necroptosis in CA1 after transient global cerebral ischemia (tGCI). However, it is still unclear whether HPC serves to regulate the phenotypic polarization of microglia/macrophages after cerebral ischemia by mitigating neuronal necroptosis. We hence aim to elucidate the underlying mechanism(s) by which the ubiquitination of RIP3-dependent necroptosis regulated by A20 affects microglia/macrophages phenotype after cerebral ischemic tolerance. We found that microglia/macrophages in CA1 of rats underwent M1 and M2 phenotypic polarization in response to tGCI. Notably, the treatment with HPC, as well as inhibitors of necroptosis, including Nec-1 and mixed lineage kinase domain-like (MLKL) siRNA, attenuated neuroinflammation associated with M1 polarization of microglia/macrophages induced by tGCI. Mechanistically, HPC was revealed to upregulate A20 and in turn enhance the interaction between A20 and RIP3, thereby reducing K63-linked polyubiquitination of RIP3 in CA1 after tGCI. Consequently, RIP3-dependent necroptosis and the M1 polarization of microglia/macrophages were blocked either by HPC or via overexpression of A20 in neurons, which ultimately mitigated cerebral injury in CA1 after tGCI. These data support that A20 serves as a crucial mediator of microglia/macrophages polarization by suppressing neuronal necroptosis in a RIP3 ubiquitination-dependent manner after tGCI. Also, a novel mechanism by which HPC functions in cerebral ischemic tolerance is elucidated.https://doi.org/10.1038/s41419-024-07293-2 |
| spellingShingle | Meiqian Qiu Wenhao Zhang Jiahua Dai Weiwen Sun Meijing Lai Shiyi Tang En Xu Yuping Ning Lixuan Zhan A20 negatively regulates necroptosis-induced microglia/macrophages polarization and mediates cerebral ischemic tolerance via inhibiting the ubiquitination of RIP3 Cell Death and Disease |
| title | A20 negatively regulates necroptosis-induced microglia/macrophages polarization and mediates cerebral ischemic tolerance via inhibiting the ubiquitination of RIP3 |
| title_full | A20 negatively regulates necroptosis-induced microglia/macrophages polarization and mediates cerebral ischemic tolerance via inhibiting the ubiquitination of RIP3 |
| title_fullStr | A20 negatively regulates necroptosis-induced microglia/macrophages polarization and mediates cerebral ischemic tolerance via inhibiting the ubiquitination of RIP3 |
| title_full_unstemmed | A20 negatively regulates necroptosis-induced microglia/macrophages polarization and mediates cerebral ischemic tolerance via inhibiting the ubiquitination of RIP3 |
| title_short | A20 negatively regulates necroptosis-induced microglia/macrophages polarization and mediates cerebral ischemic tolerance via inhibiting the ubiquitination of RIP3 |
| title_sort | a20 negatively regulates necroptosis induced microglia macrophages polarization and mediates cerebral ischemic tolerance via inhibiting the ubiquitination of rip3 |
| url | https://doi.org/10.1038/s41419-024-07293-2 |
| work_keys_str_mv | AT meiqianqiu a20negativelyregulatesnecroptosisinducedmicrogliamacrophagespolarizationandmediatescerebralischemictoleranceviainhibitingtheubiquitinationofrip3 AT wenhaozhang a20negativelyregulatesnecroptosisinducedmicrogliamacrophagespolarizationandmediatescerebralischemictoleranceviainhibitingtheubiquitinationofrip3 AT jiahuadai a20negativelyregulatesnecroptosisinducedmicrogliamacrophagespolarizationandmediatescerebralischemictoleranceviainhibitingtheubiquitinationofrip3 AT weiwensun a20negativelyregulatesnecroptosisinducedmicrogliamacrophagespolarizationandmediatescerebralischemictoleranceviainhibitingtheubiquitinationofrip3 AT meijinglai a20negativelyregulatesnecroptosisinducedmicrogliamacrophagespolarizationandmediatescerebralischemictoleranceviainhibitingtheubiquitinationofrip3 AT shiyitang a20negativelyregulatesnecroptosisinducedmicrogliamacrophagespolarizationandmediatescerebralischemictoleranceviainhibitingtheubiquitinationofrip3 AT enxu a20negativelyregulatesnecroptosisinducedmicrogliamacrophagespolarizationandmediatescerebralischemictoleranceviainhibitingtheubiquitinationofrip3 AT yupingning a20negativelyregulatesnecroptosisinducedmicrogliamacrophagespolarizationandmediatescerebralischemictoleranceviainhibitingtheubiquitinationofrip3 AT lixuanzhan a20negativelyregulatesnecroptosisinducedmicrogliamacrophagespolarizationandmediatescerebralischemictoleranceviainhibitingtheubiquitinationofrip3 |