A transient blood IL-17 increase triggers neuroinflammation in cerebellum and motor incoordination in hyperammonemic rats
Abstract Patients with liver cirrhosis may show minimal hepatic encephalopathy (MHE) with motor incoordination which is reproduced in hyperammonemic rats. Hyperammonemia induces peripheral inflammation which triggers neuroinflammation and enhanced GABAergic neurotransmission in cerebellum and motor...
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BMC
2024-11-01
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| Series: | Journal of Neuroinflammation |
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| Online Access: | https://doi.org/10.1186/s12974-024-03310-5 |
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| author | Yaiza M. Arenas Carmina Montoliu Marta Llansola Vicente Felipo |
| author_facet | Yaiza M. Arenas Carmina Montoliu Marta Llansola Vicente Felipo |
| author_sort | Yaiza M. Arenas |
| collection | DOAJ |
| description | Abstract Patients with liver cirrhosis may show minimal hepatic encephalopathy (MHE) with motor incoordination which is reproduced in hyperammonemic rats. Hyperammonemia induces peripheral inflammation which triggers neuroinflammation and enhanced GABAergic neurotransmission in cerebellum and motor incoordination. The mechanisms involved remain unknown. The aims were to assess if the early increase of peripheral IL-17 triggers motor incoordination in hyperammonemic rats and to identify some underlying mechanisms. We assessed if blocking peripheral IL-17 with anti-IL-17 at 2–4 days of hyperammonemia prevents motor incoordination and analyzed underlying mechanisms. Hyperammonemia induces a transient blood IL-17 increase at days 3–4. This is associated with increased IL-17 receptor membrane expression and activation in cerebellum, leading to NADPH oxidase activation, increased superoxide production and MLCK that induce blood–brain barrier (BBB) permeabilization by reducing occludin and ZO-1. BBB permeabilization facilitates the entry of IL-17, which increases in cerebellum and activates microglia. This increases TNFα and the TNFR1-S1PR2-CCL2-BDNF-TrkB pathway. This enhances GABAergic neurotransmission which impairs motor coordination. Blocking peripheral IL-17 with anti-IL-17 prevents all the above process and prevents motor incoordination. Early treatment to reduce blood IL-17 may be a useful treatment to reverse motor incoordination in patients with MHE. Graphical abstract |
| format | Article |
| id | doaj-art-96f9965d64294101823129b211b43f41 |
| institution | OA Journals |
| issn | 1742-2094 |
| language | English |
| publishDate | 2024-11-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Neuroinflammation |
| spelling | doaj-art-96f9965d64294101823129b211b43f412025-08-20T02:38:33ZengBMCJournal of Neuroinflammation1742-20942024-11-0121112210.1186/s12974-024-03310-5A transient blood IL-17 increase triggers neuroinflammation in cerebellum and motor incoordination in hyperammonemic ratsYaiza M. Arenas0Carmina Montoliu1Marta Llansola2Vicente Felipo3Laboratory of Neurobiology, Centro de Investigación Príncipe FelipeDepartamento de Patología, Facultad de Medicina, Universidad ValenciaLaboratory of Neurobiology, Centro de Investigación Príncipe FelipeLaboratory of Neurobiology, Centro de Investigación Príncipe FelipeAbstract Patients with liver cirrhosis may show minimal hepatic encephalopathy (MHE) with motor incoordination which is reproduced in hyperammonemic rats. Hyperammonemia induces peripheral inflammation which triggers neuroinflammation and enhanced GABAergic neurotransmission in cerebellum and motor incoordination. The mechanisms involved remain unknown. The aims were to assess if the early increase of peripheral IL-17 triggers motor incoordination in hyperammonemic rats and to identify some underlying mechanisms. We assessed if blocking peripheral IL-17 with anti-IL-17 at 2–4 days of hyperammonemia prevents motor incoordination and analyzed underlying mechanisms. Hyperammonemia induces a transient blood IL-17 increase at days 3–4. This is associated with increased IL-17 receptor membrane expression and activation in cerebellum, leading to NADPH oxidase activation, increased superoxide production and MLCK that induce blood–brain barrier (BBB) permeabilization by reducing occludin and ZO-1. BBB permeabilization facilitates the entry of IL-17, which increases in cerebellum and activates microglia. This increases TNFα and the TNFR1-S1PR2-CCL2-BDNF-TrkB pathway. This enhances GABAergic neurotransmission which impairs motor coordination. Blocking peripheral IL-17 with anti-IL-17 prevents all the above process and prevents motor incoordination. Early treatment to reduce blood IL-17 may be a useful treatment to reverse motor incoordination in patients with MHE. Graphical abstracthttps://doi.org/10.1186/s12974-024-03310-5HyperammonemiaHepatic encephalopathyMotor incoordinationIL-17Blood–brain barrierNeuroinflammation |
| spellingShingle | Yaiza M. Arenas Carmina Montoliu Marta Llansola Vicente Felipo A transient blood IL-17 increase triggers neuroinflammation in cerebellum and motor incoordination in hyperammonemic rats Journal of Neuroinflammation Hyperammonemia Hepatic encephalopathy Motor incoordination IL-17 Blood–brain barrier Neuroinflammation |
| title | A transient blood IL-17 increase triggers neuroinflammation in cerebellum and motor incoordination in hyperammonemic rats |
| title_full | A transient blood IL-17 increase triggers neuroinflammation in cerebellum and motor incoordination in hyperammonemic rats |
| title_fullStr | A transient blood IL-17 increase triggers neuroinflammation in cerebellum and motor incoordination in hyperammonemic rats |
| title_full_unstemmed | A transient blood IL-17 increase triggers neuroinflammation in cerebellum and motor incoordination in hyperammonemic rats |
| title_short | A transient blood IL-17 increase triggers neuroinflammation in cerebellum and motor incoordination in hyperammonemic rats |
| title_sort | transient blood il 17 increase triggers neuroinflammation in cerebellum and motor incoordination in hyperammonemic rats |
| topic | Hyperammonemia Hepatic encephalopathy Motor incoordination IL-17 Blood–brain barrier Neuroinflammation |
| url | https://doi.org/10.1186/s12974-024-03310-5 |
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