Chronic exposure to IL-6 induces a desensitized phenotype of the microglia

Background: When the homeostasis of the central nervous system (CNS) is altered, microglial cells become activated displaying a wide range of phenotypes that depend on the specific site, the nature of the activator, and particularly the microenvironment generated by the lesion. Cytokines are importa...

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Autores: Recasens, Mireia, Almolda, Beatriz, Pérez Clausell, Jeús, Campbell, Ian L., González, Berta, Castellano, Bernardo
Formato: artículo
Estado:Versión publicada
Fecha de publicación:2021
País:España
Recursos:Universidad de Barcelona
Repositorio:Dipòsit Digital de la UB
OAI Identifier:oai:diposit.ub.edu:2445/185930
Acesso em linha:https://hdl.handle.net/2445/185930
Access Level:acceso abierto
Palavra-chave:Cèl·lules T
Micròglia
T cells
Microglia
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spelling Chronic exposure to IL-6 induces a desensitized phenotype of the microgliaRecasens, MireiaAlmolda, BeatrizPérez Clausell, JeúsCampbell, Ian L.González, BertaCastellano, BernardoCèl·lules TMicrògliaT cellsMicrogliaBackground: When the homeostasis of the central nervous system (CNS) is altered, microglial cells become activated displaying a wide range of phenotypes that depend on the specific site, the nature of the activator, and particularly the microenvironment generated by the lesion. Cytokines are important signals involved in the modulation of the molecular microenvironment and hence play a pivotal role in orchestrating microglial activation. Among them, interleukin-6 (IL-6) is a pleiotropic cytokine described in a wide range of pathological conditions as a potent inducer and modulator of microglial activation, but with contradictory results regarding its detrimental or beneficial functions. The objective of the present study was to evaluate the effects of chronic IL-6 production on the immune response associated with CNS-axonal anterograde degeneration. Methods: The perforant pathway transection (PPT) paradigm was used in transgenic mice with astrocyte-targeted IL6-production (GFAP-IL6Tg). At 2, 3, 7, 14, and 21 days post-lesion, the hippocampal areas were processed for immunohistochemistry, flow cytometry, and protein microarray. Results: An increase in the microglia/macrophage density was observed in GFAP-IL6Tg animals in non-lesion conditions and at later time-points after PPT, associated with higher microglial proliferation and a major monocyte/macrophage cell infiltration. Besides, in homeostasis, GFAP-IL6Tg showed an environment usually linked with an innate immune response, with more perivascular CD11b+/CD45high/MHCII+/CD86+ macrophages, higher T cell infiltration, and higher IL-10, IL-13, IL-17, and IL-6 production. After PPT, WT animals show a change in microglia phenotype expressing MHCII and co-stimulatory molecules, whereas transgenic mice lack this shift. This lack of response in the GFAP-IL6Tg was associated with lower axonal sprouting. Conclusions: Chronic exposure to IL-6 induces a desensitized phenotype of the microglia.BioMed Central2021info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionapplication/pdfhttps://hdl.handle.net/2445/185930Articles publicats en revistes (Biologia Cel·lular, Fisiologia i Immunologia)reponame:Dipòsit Digital de la UBinstname:Universidad de BarcelonaInglésReproducció del document publicat a: https://doi.org/10.1186/s12974-020-02063-1Journal of Neuroinflammation, 2021, vol. 18, num. 31, p. 1-22https://doi.org/10.1186/s12974-020-02063-1cc-by (c) Recasens, Mireia et al., 2021https://creativecommons.org/licenses/by/4.0/info:eu-repo/semantics/openAccessoai:diposit.ub.edu:2445/1859302026-05-27T06:46:51Z
dc.title.none.fl_str_mv Chronic exposure to IL-6 induces a desensitized phenotype of the microglia
title Chronic exposure to IL-6 induces a desensitized phenotype of the microglia
spellingShingle Chronic exposure to IL-6 induces a desensitized phenotype of the microglia
Recasens, Mireia
Cèl·lules T
Micròglia
T cells
Microglia
title_short Chronic exposure to IL-6 induces a desensitized phenotype of the microglia
title_full Chronic exposure to IL-6 induces a desensitized phenotype of the microglia
title_fullStr Chronic exposure to IL-6 induces a desensitized phenotype of the microglia
title_full_unstemmed Chronic exposure to IL-6 induces a desensitized phenotype of the microglia
title_sort Chronic exposure to IL-6 induces a desensitized phenotype of the microglia
dc.creator.none.fl_str_mv Recasens, Mireia
Almolda, Beatriz
Pérez Clausell, Jeús
Campbell, Ian L.
González, Berta
Castellano, Bernardo
author Recasens, Mireia
author_facet Recasens, Mireia
Almolda, Beatriz
Pérez Clausell, Jeús
Campbell, Ian L.
González, Berta
Castellano, Bernardo
author_role author
author2 Almolda, Beatriz
Pérez Clausell, Jeús
Campbell, Ian L.
González, Berta
Castellano, Bernardo
author2_role author
author
author
author
author
dc.subject.none.fl_str_mv Cèl·lules T
Micròglia
T cells
Microglia
topic Cèl·lules T
Micròglia
T cells
Microglia
description Background: When the homeostasis of the central nervous system (CNS) is altered, microglial cells become activated displaying a wide range of phenotypes that depend on the specific site, the nature of the activator, and particularly the microenvironment generated by the lesion. Cytokines are important signals involved in the modulation of the molecular microenvironment and hence play a pivotal role in orchestrating microglial activation. Among them, interleukin-6 (IL-6) is a pleiotropic cytokine described in a wide range of pathological conditions as a potent inducer and modulator of microglial activation, but with contradictory results regarding its detrimental or beneficial functions. The objective of the present study was to evaluate the effects of chronic IL-6 production on the immune response associated with CNS-axonal anterograde degeneration. Methods: The perforant pathway transection (PPT) paradigm was used in transgenic mice with astrocyte-targeted IL6-production (GFAP-IL6Tg). At 2, 3, 7, 14, and 21 days post-lesion, the hippocampal areas were processed for immunohistochemistry, flow cytometry, and protein microarray. Results: An increase in the microglia/macrophage density was observed in GFAP-IL6Tg animals in non-lesion conditions and at later time-points after PPT, associated with higher microglial proliferation and a major monocyte/macrophage cell infiltration. Besides, in homeostasis, GFAP-IL6Tg showed an environment usually linked with an innate immune response, with more perivascular CD11b+/CD45high/MHCII+/CD86+ macrophages, higher T cell infiltration, and higher IL-10, IL-13, IL-17, and IL-6 production. After PPT, WT animals show a change in microglia phenotype expressing MHCII and co-stimulatory molecules, whereas transgenic mice lack this shift. This lack of response in the GFAP-IL6Tg was associated with lower axonal sprouting. Conclusions: Chronic exposure to IL-6 induces a desensitized phenotype of the microglia.
publishDate 2021
dc.date.none.fl_str_mv 2021
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/2445/185930
url https://hdl.handle.net/2445/185930
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv Reproducció del document publicat a: https://doi.org/10.1186/s12974-020-02063-1
Journal of Neuroinflammation, 2021, vol. 18, num. 31, p. 1-22
https://doi.org/10.1186/s12974-020-02063-1
dc.rights.none.fl_str_mv cc-by (c) Recasens, Mireia et al., 2021
https://creativecommons.org/licenses/by/4.0/
info:eu-repo/semantics/openAccess
rights_invalid_str_mv cc-by (c) Recasens, Mireia et al., 2021
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 BioMed Central
publisher.none.fl_str_mv BioMed Central
dc.source.none.fl_str_mv Articles publicats en revistes (Biologia Cel·lular, Fisiologia i Immunologia)
reponame:Dipòsit Digital de la UB
instname:Universidad de Barcelona
instname_str Universidad de Barcelona
reponame_str Dipòsit Digital de la UB
collection Dipòsit Digital de la UB
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15.301603

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