Nigrostriatal degeneration determines dynamics of glial inflammatory and phagocytic activity

Glial cells are key players in the initiation of innate immunity in neurodegeneration. Upon damage, they switch their basal activation state and acquire new functions in a context and time-dependent manner. Since modulation of neuroinflammation is becoming an interesting approach for the treatment o...

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Authors: Ayerra, Leyre, Abellanas, Miguel Ángel, Basurco, Leyre, Tamayo Uria, Ibon, Conde, Enrique, Tavira, Adriana, Trigo, Amaya, Vidaurre, Clara, Vilas, Amaia, San Martin-Uriz, Patxi, Luquin, Esther, Clavero Ibarra, Pedro Luis, Mengual, Elisa, Aymerich, María Soledad
Format: article
Status:Published version
Publication Date:2024
Country:España
Institution:Universidad Pública de Navarra
Repository:Academica-e. Repositorio Institucional de la Universidad Pública de Navarra
OAI Identifier:oai:academica-e.unavarra.es:2454/50248
Online Access:https://hdl.handle.net/2454/50248
Access Level:Open access
Keyword:Parkinson&apos
s disease
Microglia
Neurodegeneration
Phagocytosis
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spelling Nigrostriatal degeneration determines dynamics of glial inflammatory and phagocytic activityAyerra, LeyreAbellanas, Miguel ÁngelBasurco, LeyreTamayo Uria, IbonConde, EnriqueTavira, AdrianaTrigo, AmayaVidaurre, ClaraVilas, AmaiaSan Martin-Uriz, PatxiLuquin, EstherClavero Ibarra, Pedro LuisMengual, ElisaAymerich, María SoledadParkinson&aposs diseaseMicrogliaNeurodegenerationPhagocytosisGlial cells are key players in the initiation of innate immunity in neurodegeneration. Upon damage, they switch their basal activation state and acquire new functions in a context and time-dependent manner. Since modulation of neuroinflammation is becoming an interesting approach for the treatment of neurodegenerative diseases, it is crucial to understand the specific contribution of these cells to the inflammatory reaction and to select experimental models that recapitulate what occurs in the human disease. Previously, we have characterized a region-specific activation pattern of CD11b(+) cells and astrocytes in the alpha-synuclein overexpression mouse model of Parkinsons disease (PD). In this study we hypothesized that the time and the intensity of dopaminergic neuronal death would promote different glial activation states. Dopaminergic degeneration was induced with two administration regimens of the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), subacute (sMPTP) and chronic (cMPTP). Our results show that in the sMPTP mouse model, the pro-inflammatory phenotype of striatal CD11b(+) cells was counteracted by an anti-inflammatory astrocytic profile. In the midbrain the roles were inverted, CD11b(+) cells exhibited an anti-inflammatory profile and astrocytes were pro-inflammatory. The overall response generated resulted in decreased CD4 T cell infiltration in both regions. Chronic MPTP exposure resulted in a mild and prolonged neuronal degeneration that generated a pro-inflammatory response and increased CD4 T cell infiltration in both regions. At the onset of the neurodegenerative process, microglia and astrocytes cooperated in the removal of dopaminergic terminals. With time, only microglia maintained the phagocytic activity. In the ventral midbrain, astrocytes were the main phagocytic mediators at early stages of degeneration while microglia were the major phagocytic cells in the chronic state. In this scenario, we questioned which activation pattern recapitulates better the features of glial activation in PD. Glial activation in the cMPTP mouse model reflects many pathways of their corresponding counterparts in the human brain with advanced PD. Altogether, our results point toward a context-dependent cooperativity of microglia/myeloid cells and astrocytes in response to neuronal damage and the relevance of selecting the right experimental models for the study of neuroinflammation.This work was supported by the Spanish Government (ISCIII-FEDER) PI20/01063, by Navarra Government (PC 060–061 and PC 192–193) and Fundación Gangoiti. LA was funded by FPU19/03255, LB was funded by FPU: FPU018/02244; AT was funded by FPU21/01545.BMCCiencias de la SaludOsasun Zientziak2024info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionapplication/pdfhttps://hdl.handle.net/2454/50248reponame:Academica-e. Repositorio Institucional de la Universidad Pública de Navarrainstname:Universidad Pública de NavarraInglésinfo:eu-repo/grantAgreement/ISCIII/Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020 (ISCIII)/PI20%2F01063info:eu-repo/grantAgreement/Gobierno de Navarra//PC 060–061info:eu-repo/grantAgreement/Gobierno de Navarra//PC 192–193© The Author(s) 2024. This article is licensed under a Creative Commons Attribution 4.0 International License. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.https://creativecommons.org/licenses/by/4.0/info:eu-repo/semantics/openAccessoai:academica-e.unavarra.es:2454/502482026-06-17T12:41:47Z
dc.title.none.fl_str_mv Nigrostriatal degeneration determines dynamics of glial inflammatory and phagocytic activity
title Nigrostriatal degeneration determines dynamics of glial inflammatory and phagocytic activity
spellingShingle Nigrostriatal degeneration determines dynamics of glial inflammatory and phagocytic activity
Ayerra, Leyre
Parkinson&apos
s disease
Microglia
Neurodegeneration
Phagocytosis
title_short Nigrostriatal degeneration determines dynamics of glial inflammatory and phagocytic activity
title_full Nigrostriatal degeneration determines dynamics of glial inflammatory and phagocytic activity
title_fullStr Nigrostriatal degeneration determines dynamics of glial inflammatory and phagocytic activity
title_full_unstemmed Nigrostriatal degeneration determines dynamics of glial inflammatory and phagocytic activity
title_sort Nigrostriatal degeneration determines dynamics of glial inflammatory and phagocytic activity
dc.creator.none.fl_str_mv Ayerra, Leyre
Abellanas, Miguel Ángel
Basurco, Leyre
Tamayo Uria, Ibon
Conde, Enrique
Tavira, Adriana
Trigo, Amaya
Vidaurre, Clara
Vilas, Amaia
San Martin-Uriz, Patxi
Luquin, Esther
Clavero Ibarra, Pedro Luis
Mengual, Elisa
Aymerich, María Soledad
author Ayerra, Leyre
author_facet Ayerra, Leyre
Abellanas, Miguel Ángel
Basurco, Leyre
Tamayo Uria, Ibon
Conde, Enrique
Tavira, Adriana
Trigo, Amaya
Vidaurre, Clara
Vilas, Amaia
San Martin-Uriz, Patxi
Luquin, Esther
Clavero Ibarra, Pedro Luis
Mengual, Elisa
Aymerich, María Soledad
author_role author
author2 Abellanas, Miguel Ángel
Basurco, Leyre
Tamayo Uria, Ibon
Conde, Enrique
Tavira, Adriana
Trigo, Amaya
Vidaurre, Clara
Vilas, Amaia
San Martin-Uriz, Patxi
Luquin, Esther
Clavero Ibarra, Pedro Luis
Mengual, Elisa
Aymerich, María Soledad
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
dc.contributor.none.fl_str_mv Ciencias de la Salud
Osasun Zientziak
dc.subject.none.fl_str_mv Parkinson&apos
s disease
Microglia
Neurodegeneration
Phagocytosis
topic Parkinson&apos
s disease
Microglia
Neurodegeneration
Phagocytosis
description Glial cells are key players in the initiation of innate immunity in neurodegeneration. Upon damage, they switch their basal activation state and acquire new functions in a context and time-dependent manner. Since modulation of neuroinflammation is becoming an interesting approach for the treatment of neurodegenerative diseases, it is crucial to understand the specific contribution of these cells to the inflammatory reaction and to select experimental models that recapitulate what occurs in the human disease. Previously, we have characterized a region-specific activation pattern of CD11b(+) cells and astrocytes in the alpha-synuclein overexpression mouse model of Parkinsons disease (PD). In this study we hypothesized that the time and the intensity of dopaminergic neuronal death would promote different glial activation states. Dopaminergic degeneration was induced with two administration regimens of the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), subacute (sMPTP) and chronic (cMPTP). Our results show that in the sMPTP mouse model, the pro-inflammatory phenotype of striatal CD11b(+) cells was counteracted by an anti-inflammatory astrocytic profile. In the midbrain the roles were inverted, CD11b(+) cells exhibited an anti-inflammatory profile and astrocytes were pro-inflammatory. The overall response generated resulted in decreased CD4 T cell infiltration in both regions. Chronic MPTP exposure resulted in a mild and prolonged neuronal degeneration that generated a pro-inflammatory response and increased CD4 T cell infiltration in both regions. At the onset of the neurodegenerative process, microglia and astrocytes cooperated in the removal of dopaminergic terminals. With time, only microglia maintained the phagocytic activity. In the ventral midbrain, astrocytes were the main phagocytic mediators at early stages of degeneration while microglia were the major phagocytic cells in the chronic state. In this scenario, we questioned which activation pattern recapitulates better the features of glial activation in PD. Glial activation in the cMPTP mouse model reflects many pathways of their corresponding counterparts in the human brain with advanced PD. Altogether, our results point toward a context-dependent cooperativity of microglia/myeloid cells and astrocytes in response to neuronal damage and the relevance of selecting the right experimental models for the study of neuroinflammation.
publishDate 2024
dc.date.none.fl_str_mv 2024
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv https://hdl.handle.net/2454/50248
url https://hdl.handle.net/2454/50248
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv info:eu-repo/grantAgreement/ISCIII/Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020 (ISCIII)/PI20%2F01063
info:eu-repo/grantAgreement/Gobierno de Navarra//PC 060–061
info:eu-repo/grantAgreement/Gobierno de Navarra//PC 192–193
dc.rights.none.fl_str_mv https://creativecommons.org/licenses/by/4.0/
info:eu-repo/semantics/openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by/4.0/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv BMC
publisher.none.fl_str_mv BMC
dc.source.none.fl_str_mv reponame:Academica-e. Repositorio Institucional de la Universidad Pública de Navarra
instname:Universidad Pública de Navarra
instname_str Universidad Pública de Navarra
reponame_str Academica-e. Repositorio Institucional de la Universidad Pública de Navarra
collection Academica-e. Repositorio Institucional de la Universidad Pública de Navarra
repository.name.fl_str_mv
repository.mail.fl_str_mv
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