Human Microglia-Like Cells Differentiated from Monocytes with GM-CSF and IL-34 Show Phagocytosis of α-Synuclein Aggregates and C/EBPβ-Dependent Proinflammatory Activation

Microglia, the main resident immune cells in the central nervous system, are implicated in the pathogenesis of various neurological disorders. Much of our knowledge on microglial biology was obtained using rodent microglial cultures. To understand the role of microglia in human disease, reliable in...

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Autores: Llaves-López, Andrea, Micoli, Elia, Belmonte-Mateos, Carla, Aguilar, Gerard, Alba, Clara, Marsal, Anais, Pulido-Salgado, Marta, Rabaneda-Lombarte, Neus, Solà, Carme, Serratosa, Joan, Vidal-Taboada, Jose M., Saura, Josep
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2025
País:España
Institución:Consejo Superior de Investigaciones Científicas (CSIC)
Repositorio:DIGITAL.CSIC. Repositorio Institucional del CSIC
OAI Identifier:oai:digital.csic.es:10261/384407
Acceso en línea:http://hdl.handle.net/10261/384407
https://api.elsevier.com/content/abstract/scopus_id/85196371747
Access Level:acceso abierto
Palabra clave:C/EBPbeta
Cell culture
In vitro model
Microglia
Monocyte-derived
Neuroinflammation
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spelling Human Microglia-Like Cells Differentiated from Monocytes with GM-CSF and IL-34 Show Phagocytosis of α-Synuclein Aggregates and C/EBPβ-Dependent Proinflammatory ActivationLlaves-López, AndreaMicoli, EliaBelmonte-Mateos, CarlaAguilar, GerardAlba, ClaraMarsal, AnaisPulido-Salgado, MartaRabaneda-Lombarte, NeusSolà, CarmeSerratosa, JoanVidal-Taboada, Jose M.Saura, JosepC/EBPbetaCell cultureIn vitro modelMicrogliaMonocyte-derivedNeuroinflammationMicroglia, the main resident immune cells in the central nervous system, are implicated in the pathogenesis of various neurological disorders. Much of our knowledge on microglial biology was obtained using rodent microglial cultures. To understand the role of microglia in human disease, reliable in vitro models of human microglia are necessary. Monocyte-derived microglia-like cells (MDMi) are a promising approach. This study aimed to characterize MDMi cells generated from adult human monocytes using granulocyte-macrophage colony-stimulating factor and interleukin-34. To this end, 49 independent cultures of MDMI were prepared, and various methodological and functional studies were performed. We show that with this protocol, adult human monocytes develop into microglia-like cells, a coating is unnecessary, and high cell density seeding is preferable. When compared to monocytes, MDMi upregulate the expression of many, but not all, microglial markers, indicating that, although these cells display a microglia-like phenotype, they cannot be considered bona fide human microglia. At the functional level, MDMi phagocytose α-synuclein aggregates and responds to lipopolysaccharide (LPS) by nuclear translocation of the transcription factor nuclear factor-kappaB (NFkappaB) and the upregulation of proinflammatory genes. Finally, a long-lasting silencing of the transcription factor CCAAT/enhancer protein β (C/EBPβ) was achieved by small interfering RNA, resulting in the subsequent downregulation of proinflammatory genes. This supports the hypothesis that C/EBPβ plays a key role in proinflammatory gene program activation in human microglia. Altogether, this study sheds new light on the properties of MDMi cells and supports these cells as a promising in vitro model for studying adult human microglia-like cells.Open Access funding provided thanks to the CRUE-CSIC agreement with Springer Nature. This study was supported by grants PI14/00302 and PI19/00593 from the Instituto de Salud Carlos III (Spain) with joint financing by FEDER funds from the European Union.Peer reviewedSpringer NatureConferencia de Rectores de las Universidades EspañolasConsejo Superior de Investigaciones Científicas (España)Instituto de Salud Carlos IIIEuropean CommissionLlaves-López, Andrea [0000-0002-7726-1642]Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]202520252025info:eu-repo/semantics/articlehttp://purl.org/coar/resource_type/c_6501Publisher's versioninfo:eu-repo/semantics/publishedVersionapplication/pdfhttp://hdl.handle.net/10261/384407https://api.elsevier.com/content/abstract/scopus_id/85196371747reponame:DIGITAL.CSIC. Repositorio Institucional del CSICinstname:Consejo Superior de Investigaciones Científicas (CSIC)Ingléshttps://doi.org/10.1007/s12035-024-04289-zSíinfo:eu-repo/semantics/openAccessoai:digital.csic.es:10261/3844072026-05-22T06:33:51Z
dc.title.none.fl_str_mv Human Microglia-Like Cells Differentiated from Monocytes with GM-CSF and IL-34 Show Phagocytosis of α-Synuclein Aggregates and C/EBPβ-Dependent Proinflammatory Activation
title Human Microglia-Like Cells Differentiated from Monocytes with GM-CSF and IL-34 Show Phagocytosis of α-Synuclein Aggregates and C/EBPβ-Dependent Proinflammatory Activation
spellingShingle Human Microglia-Like Cells Differentiated from Monocytes with GM-CSF and IL-34 Show Phagocytosis of α-Synuclein Aggregates and C/EBPβ-Dependent Proinflammatory Activation
Llaves-López, Andrea
C/EBPbeta
Cell culture
In vitro model
Microglia
Monocyte-derived
Neuroinflammation
title_short Human Microglia-Like Cells Differentiated from Monocytes with GM-CSF and IL-34 Show Phagocytosis of α-Synuclein Aggregates and C/EBPβ-Dependent Proinflammatory Activation
title_full Human Microglia-Like Cells Differentiated from Monocytes with GM-CSF and IL-34 Show Phagocytosis of α-Synuclein Aggregates and C/EBPβ-Dependent Proinflammatory Activation
title_fullStr Human Microglia-Like Cells Differentiated from Monocytes with GM-CSF and IL-34 Show Phagocytosis of α-Synuclein Aggregates and C/EBPβ-Dependent Proinflammatory Activation
title_full_unstemmed Human Microglia-Like Cells Differentiated from Monocytes with GM-CSF and IL-34 Show Phagocytosis of α-Synuclein Aggregates and C/EBPβ-Dependent Proinflammatory Activation
title_sort Human Microglia-Like Cells Differentiated from Monocytes with GM-CSF and IL-34 Show Phagocytosis of α-Synuclein Aggregates and C/EBPβ-Dependent Proinflammatory Activation
dc.creator.none.fl_str_mv Llaves-López, Andrea
Micoli, Elia
Belmonte-Mateos, Carla
Aguilar, Gerard
Alba, Clara
Marsal, Anais
Pulido-Salgado, Marta
Rabaneda-Lombarte, Neus
Solà, Carme
Serratosa, Joan
Vidal-Taboada, Jose M.
Saura, Josep
author Llaves-López, Andrea
author_facet Llaves-López, Andrea
Micoli, Elia
Belmonte-Mateos, Carla
Aguilar, Gerard
Alba, Clara
Marsal, Anais
Pulido-Salgado, Marta
Rabaneda-Lombarte, Neus
Solà, Carme
Serratosa, Joan
Vidal-Taboada, Jose M.
Saura, Josep
author_role author
author2 Micoli, Elia
Belmonte-Mateos, Carla
Aguilar, Gerard
Alba, Clara
Marsal, Anais
Pulido-Salgado, Marta
Rabaneda-Lombarte, Neus
Solà, Carme
Serratosa, Joan
Vidal-Taboada, Jose M.
Saura, Josep
author2_role author
author
author
author
author
author
author
author
author
author
author
dc.contributor.none.fl_str_mv Conferencia de Rectores de las Universidades Españolas
Consejo Superior de Investigaciones Científicas (España)
Instituto de Salud Carlos III
European Commission
Llaves-López, Andrea [0000-0002-7726-1642]
Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]
dc.subject.none.fl_str_mv C/EBPbeta
Cell culture
In vitro model
Microglia
Monocyte-derived
Neuroinflammation
topic C/EBPbeta
Cell culture
In vitro model
Microglia
Monocyte-derived
Neuroinflammation
description Microglia, the main resident immune cells in the central nervous system, are implicated in the pathogenesis of various neurological disorders. Much of our knowledge on microglial biology was obtained using rodent microglial cultures. To understand the role of microglia in human disease, reliable in vitro models of human microglia are necessary. Monocyte-derived microglia-like cells (MDMi) are a promising approach. This study aimed to characterize MDMi cells generated from adult human monocytes using granulocyte-macrophage colony-stimulating factor and interleukin-34. To this end, 49 independent cultures of MDMI were prepared, and various methodological and functional studies were performed. We show that with this protocol, adult human monocytes develop into microglia-like cells, a coating is unnecessary, and high cell density seeding is preferable. When compared to monocytes, MDMi upregulate the expression of many, but not all, microglial markers, indicating that, although these cells display a microglia-like phenotype, they cannot be considered bona fide human microglia. At the functional level, MDMi phagocytose α-synuclein aggregates and responds to lipopolysaccharide (LPS) by nuclear translocation of the transcription factor nuclear factor-kappaB (NFkappaB) and the upregulation of proinflammatory genes. Finally, a long-lasting silencing of the transcription factor CCAAT/enhancer protein β (C/EBPβ) was achieved by small interfering RNA, resulting in the subsequent downregulation of proinflammatory genes. This supports the hypothesis that C/EBPβ plays a key role in proinflammatory gene program activation in human microglia. Altogether, this study sheds new light on the properties of MDMi cells and supports these cells as a promising in vitro model for studying adult human microglia-like cells.
publishDate 2025
dc.date.none.fl_str_mv 2025
2025
2025
dc.type.none.fl_str_mv info:eu-repo/semantics/article
http://purl.org/coar/resource_type/c_6501
Publisher's version
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/10261/384407
https://api.elsevier.com/content/abstract/scopus_id/85196371747
url http://hdl.handle.net/10261/384407
https://api.elsevier.com/content/abstract/scopus_id/85196371747
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv https://doi.org/10.1007/s12035-024-04289-z
Sí
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv Springer Nature
publisher.none.fl_str_mv Springer Nature
dc.source.none.fl_str_mv reponame:DIGITAL.CSIC. Repositorio Institucional del CSIC
instname:Consejo Superior de Investigaciones Científicas (CSIC)
instname_str Consejo Superior de Investigaciones Científicas (CSIC)
reponame_str DIGITAL.CSIC. Repositorio Institucional del CSIC
collection DIGITAL.CSIC. Repositorio Institucional del CSIC
repository.name.fl_str_mv
repository.mail.fl_str_mv
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