Increased levels and activation of the IL-17 receptor in microglia contribute to enhanced neuroinflammation in cerebellum of hyperammonemic rats

Background Patients with liver cirrhosis may show minimal hepatic encephalopathy (MHE) with mild cognitive impairment and motor incoordination. Rats with chronic hyperammonemia reproduce these alterations. Motor incoordination in hyperammonemic rats is due to increased GABAergic neurotransmission in...

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Autores: Arenas YM, López-Gramaje A, Montoliu C, Llansola M, Felipo V
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2024
País:España
Institución:INCLIVA
Repositorio:r-INCLIVA. Repositorio Institucional de Producción Científica de INCLIVA
OAI Identifier:oai:incliva.fundanetsuite.com:p18217
Acceso en línea:https://incliva.portalinvestigacion.com/publicaciones/18217
Access Level:acceso abierto
Palabra clave:Cerebellum
Hyperammonemia
IL-17
Neuroinflammation
Microglia
Hepatic encephalopathy
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spelling Increased levels and activation of the IL-17 receptor in microglia contribute to enhanced neuroinflammation in cerebellum of hyperammonemic rats Arenas YM López-Gramaje A Montoliu C Llansola M Felipo V Cerebellum Hyperammonemia IL-17 Neuroinflammation Microglia Hepatic encephalopathy Background Patients with liver cirrhosis may show minimal hepatic encephalopathy (MHE) with mild cognitive impairment and motor incoordination. Rats with chronic hyperammonemia reproduce these alterations. Motor incoordination in hyperammonemic rats is due to increased GABAergic neurotransmission in cerebellum, induced by neuroinflammation, which enhances TNF alpha-TNFR1-S1PR2-CCL2-BDNF-TrkB pathway activation. The initial events by which hyperammonemia triggers activation of this pathway remain unclear. MHE in cirrhotic patients is triggered by a shift in inflammation with increased IL-17. The aims of this work were: (1) assess if hyperammonemia increases IL-17 content and membrane expression of its receptor in cerebellum of hyperammonemic rats; (2) identify the cell types in which IL-17 receptor is expressed and IL-17 increases in hyperammonemia; (3) assess if blocking IL-17 signaling with anti-IL-17 ex-vivo reverses activation of glia and of the TNF alpha-TNFR1-S1PR2-CCL2-BDNF-TrkB pathway.Results IL-17 levels and membrane expression of the IL-17 receptor are increased in cerebellum of rats with hyperammonemia and MHE, leading to increased activation of IL-17 receptor in microglia, which triggers activation of STAT3 and NF-kB, increasing IL-17 and TNF alpha levels, respectively. TNF alpha released from microglia activates TNFR1 in Purkinje neurons, leading to activation of NF-kB and increased IL-17 and TNF alpha also in these cells. Enhanced TNFR1 activation also enhances activation of the TNFR1-S1PR2-CCL2-BDNF-TrkB pathway which mediates microglia and astrocytes activation.Conclusions All these steps are triggered by enhanced activation of IL-17 receptor in microglia and are prevented by ex-vivo treatment with anti-IL-17. IL-17 and IL-17 receptor in microglia would be therapeutic targets to treat neurological impairment in patients with MHE. SOC BIOLGIA CHILE https://incliva.portalinvestigacion.com/publicaciones/18217
title Increased levels and activation of the IL-17 receptor in microglia contribute to enhanced neuroinflammation in cerebellum of hyperammonemic rats
spellingShingle Increased levels and activation of the IL-17 receptor in microglia contribute to enhanced neuroinflammation in cerebellum of hyperammonemic rats
Arenas YM
Cerebellum
Hyperammonemia
IL-17
Neuroinflammation
Microglia
Hepatic encephalopathy
title_short Increased levels and activation of the IL-17 receptor in microglia contribute to enhanced neuroinflammation in cerebellum of hyperammonemic rats
title_full Increased levels and activation of the IL-17 receptor in microglia contribute to enhanced neuroinflammation in cerebellum of hyperammonemic rats
title_fullStr Increased levels and activation of the IL-17 receptor in microglia contribute to enhanced neuroinflammation in cerebellum of hyperammonemic rats
title_full_unstemmed Increased levels and activation of the IL-17 receptor in microglia contribute to enhanced neuroinflammation in cerebellum of hyperammonemic rats
title_sort Increased levels and activation of the IL-17 receptor in microglia contribute to enhanced neuroinflammation in cerebellum of hyperammonemic rats
author Arenas YM
author_facet Arenas YM
López-Gramaje A
Montoliu C
Llansola M
Felipo V
author_role author
author2 López-Gramaje A
Montoliu C
Llansola M
Felipo V
author2_role author
author
author
author
topic Cerebellum
Hyperammonemia
IL-17
Neuroinflammation
Microglia
Hepatic encephalopathy
topic_facet Cerebellum
Hyperammonemia
IL-17
Neuroinflammation
Microglia
Hepatic encephalopathy
description Background Patients with liver cirrhosis may show minimal hepatic encephalopathy (MHE) with mild cognitive impairment and motor incoordination. Rats with chronic hyperammonemia reproduce these alterations. Motor incoordination in hyperammonemic rats is due to increased GABAergic neurotransmission in cerebellum, induced by neuroinflammation, which enhances TNF alpha-TNFR1-S1PR2-CCL2-BDNF-TrkB pathway activation. The initial events by which hyperammonemia triggers activation of this pathway remain unclear. MHE in cirrhotic patients is triggered by a shift in inflammation with increased IL-17. The aims of this work were: (1) assess if hyperammonemia increases IL-17 content and membrane expression of its receptor in cerebellum of hyperammonemic rats; (2) identify the cell types in which IL-17 receptor is expressed and IL-17 increases in hyperammonemia; (3) assess if blocking IL-17 signaling with anti-IL-17 ex-vivo reverses activation of glia and of the TNF alpha-TNFR1-S1PR2-CCL2-BDNF-TrkB pathway.Results IL-17 levels and membrane expression of the IL-17 receptor are increased in cerebellum of rats with hyperammonemia and MHE, leading to increased activation of IL-17 receptor in microglia, which triggers activation of STAT3 and NF-kB, increasing IL-17 and TNF alpha levels, respectively. TNF alpha released from microglia activates TNFR1 in Purkinje neurons, leading to activation of NF-kB and increased IL-17 and TNF alpha also in these cells. Enhanced TNFR1 activation also enhances activation of the TNFR1-S1PR2-CCL2-BDNF-TrkB pathway which mediates microglia and astrocytes activation.Conclusions All these steps are triggered by enhanced activation of IL-17 receptor in microglia and are prevented by ex-vivo treatment with anti-IL-17. IL-17 and IL-17 receptor in microglia would be therapeutic targets to treat neurological impairment in patients with MHE.
publishDate 2024
format article
status_str publishedVersion
url https://incliva.portalinvestigacion.com/publicaciones/18217
eu_rights_str_mv openAccess
publisher SOC BIOLGIA CHILE
institution INCLIVA
collection r-INCLIVA. Repositorio Institucional de Producción Científica de INCLIVA
reponame_str r-INCLIVA. Repositorio Institucional de Producción Científica de INCLIVA
instname_str INCLIVA
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publishDateSort 2024
author_browse Arenas YM
Felipo V
Llansola M
López-Gramaje A
Montoliu C
publisherStr SOC BIOLGIA CHILE
score 6.924472

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