Microglia Susceptibility to Free Bilirubin Is Age-Dependent

Detalhes bibliográficos
Autor(a) principal: Vaz, Ana Rita
Data de Publicação: 2020
Outros Autores: Falcão, Ana Sofia, Scarpa, Eleonora, Semproni, Carlotta, Brites, Dora
Tipo de documento: Artigo
Idioma: eng
Título da fonte: Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
Texto Completo: http://hdl.handle.net/10362/105761
Resumo: Funding: This work was supported by National Funds (Fundacão para a Ciencia e a Tecnologia—UID/DTP/04138/2015-2019) to iMed.ULisboa. AF had a post-doctoral research position (C2007-FFUL/UBMBE/02/ 2011) and AV a post-doc fellowship (SFRH/BPD/76590/2011), both granted by FCT. CS and ES were Master students from University of Bologna who developed their thesis at Universidade de Lisboa, with fellowships from Erasmus+ Programme. We thank Professor Stefano Girotti from the University of Bologna for establishing such collaborative Program and for the local supervision of the students. The funding organization had no role in data collection and analysis, decision to publish, or preparation of the manuscrip
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spelling Microglia Susceptibility to Free Bilirubin Is Age-Dependentinflammatory-miRNAsmicroglia inflammatory responsepro- and anti-inflammatory markersunconjugated bilirubinyoung and aged cultured microgliaPharmacologyPharmacology (medical)Funding: This work was supported by National Funds (Fundacão para a Ciencia e a Tecnologia—UID/DTP/04138/2015-2019) to iMed.ULisboa. AF had a post-doctoral research position (C2007-FFUL/UBMBE/02/ 2011) and AV a post-doc fellowship (SFRH/BPD/76590/2011), both granted by FCT. CS and ES were Master students from University of Bologna who developed their thesis at Universidade de Lisboa, with fellowships from Erasmus+ Programme. We thank Professor Stefano Girotti from the University of Bologna for establishing such collaborative Program and for the local supervision of the students. The funding organization had no role in data collection and analysis, decision to publish, or preparation of the manuscripIncreased concentrations of unconjugated bilirubin (UCB), namely its free fraction (Bf), in neonatal life may cause transient or definitive injury to neurons and glial cells. We demonstrated that UCB damages neurons and glial cells by compromising oligodendrocyte maturation and myelination, and by activating astrocytes and microglia. Immature neurons and astrocytes showed to be especially vulnerable. However, whether microglia susceptibility to UCB is also age-related was never investigated. We developed a microglia culture model in which cells at 2 days in vitro (2DIV) revealed to behave as the neonatal microglia (amoeboid/reactive cells), in contrast with those at 16DIV microglia that performed as aged cells (irresponsive/dormant cells). Here, we aimed to unveil whether UCB-induced toxicity diverged from the young to the long-cultured microglia. Cells were isolated from the cortical brain of 1- to 2-day-old CD1 mice and incubated for 24 h with 50/100 nM Bf levels, which were associated to moderate and severe neonatal hyperbilirubinemia, respectively. These concentrations of Bf induced early apoptosis and amoeboid shape in 2DIV microglia, while caused late apoptosis in 16DIV cells, without altering their morphology. CD11b staining increased in both, but more markedly in 2DIV cells. Likewise, the gene expression of HMGB1, a well-known alarmin, as well as HMGB1 and GLT-1–positive cells, were enhanced as compared to long-maturated microglia. The CX3CR1 reduction in 2DIV microglia was opposed to the 16DIV cells and suggests a preferential Bf-induced sickness response in younger cells. In conformity, increased mitochondrial mass and NO were enhanced in 2DIV cells, but unchanged or reduced, respectively, in the 16DIV microglia. However, 100 nM Bf caused iNOS gene overexpression in 2DIV and 16DIV cells. While only arginase 1/IL-1β gene expression levels increased upon 50/100 nM Bf treatment in long-maturated microglia, MHCII/arginase 1/TNF-α/IL-1β/IL-6 (>10-fold) were upregulated in the 2DIV microglia. Remarkably, enhanced inflammatory-associated microRNAs (miR-155/miR-125b/miR-21/miR-146a) and reduced anti-inflammatory miR-124 were found in young microglia by both Bf concentrations, while remained unchanged (miR/21/miR-125b) or decreased (miR-155/miR-146a/miR-124) in aged cells. Altogether, these findings support the neurodevelopmental susceptibilities to UCB-induced neurotoxicity, the most severe disabilities in premature babies, and the involvement of immune-inflammation neonatal microglia processes in poorer outcomes.Centro de Estudos de Doenças Crónicas (CEDOC)NOVA Medical School|Faculdade de Ciências Médicas (NMS|FCM)RUNVaz, Ana RitaFalcão, Ana SofiaScarpa, EleonoraSemproni, CarlottaBrites, Dora2020-10-17T00:19:29Z2020-07-142020-07-14T00:00:00Zinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articleapplication/pdfhttp://hdl.handle.net/10362/105761eng1663-9812PURE: 19979168https://doi.org/10.3389/fphar.2020.01012info:eu-repo/semantics/openAccessreponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãoinstacron:RCAAP2024-03-11T04:50:59Zoai:run.unl.pt:10362/105761Portal AgregadorONGhttps://www.rcaap.pt/oai/openaireopendoar:71602024-03-20T03:40:35.271924Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãofalse
dc.title.none.fl_str_mv Microglia Susceptibility to Free Bilirubin Is Age-Dependent
title Microglia Susceptibility to Free Bilirubin Is Age-Dependent
spellingShingle Microglia Susceptibility to Free Bilirubin Is Age-Dependent
Vaz, Ana Rita
inflammatory-miRNAs
microglia inflammatory response
pro- and anti-inflammatory markers
unconjugated bilirubin
young and aged cultured microglia
Pharmacology
Pharmacology (medical)
title_short Microglia Susceptibility to Free Bilirubin Is Age-Dependent
title_full Microglia Susceptibility to Free Bilirubin Is Age-Dependent
title_fullStr Microglia Susceptibility to Free Bilirubin Is Age-Dependent
title_full_unstemmed Microglia Susceptibility to Free Bilirubin Is Age-Dependent
title_sort Microglia Susceptibility to Free Bilirubin Is Age-Dependent
author Vaz, Ana Rita
author_facet Vaz, Ana Rita
Falcão, Ana Sofia
Scarpa, Eleonora
Semproni, Carlotta
Brites, Dora
author_role author
author2 Falcão, Ana Sofia
Scarpa, Eleonora
Semproni, Carlotta
Brites, Dora
author2_role author
author
author
author
dc.contributor.none.fl_str_mv Centro de Estudos de Doenças Crónicas (CEDOC)
NOVA Medical School|Faculdade de Ciências Médicas (NMS|FCM)
RUN
dc.contributor.author.fl_str_mv Vaz, Ana Rita
Falcão, Ana Sofia
Scarpa, Eleonora
Semproni, Carlotta
Brites, Dora
dc.subject.por.fl_str_mv inflammatory-miRNAs
microglia inflammatory response
pro- and anti-inflammatory markers
unconjugated bilirubin
young and aged cultured microglia
Pharmacology
Pharmacology (medical)
topic inflammatory-miRNAs
microglia inflammatory response
pro- and anti-inflammatory markers
unconjugated bilirubin
young and aged cultured microglia
Pharmacology
Pharmacology (medical)
description Funding: This work was supported by National Funds (Fundacão para a Ciencia e a Tecnologia—UID/DTP/04138/2015-2019) to iMed.ULisboa. AF had a post-doctoral research position (C2007-FFUL/UBMBE/02/ 2011) and AV a post-doc fellowship (SFRH/BPD/76590/2011), both granted by FCT. CS and ES were Master students from University of Bologna who developed their thesis at Universidade de Lisboa, with fellowships from Erasmus+ Programme. We thank Professor Stefano Girotti from the University of Bologna for establishing such collaborative Program and for the local supervision of the students. The funding organization had no role in data collection and analysis, decision to publish, or preparation of the manuscrip
publishDate 2020
dc.date.none.fl_str_mv 2020-10-17T00:19:29Z
2020-07-14
2020-07-14T00:00:00Z
dc.type.status.fl_str_mv info:eu-repo/semantics/publishedVersion
dc.type.driver.fl_str_mv info:eu-repo/semantics/article
format article
status_str publishedVersion
dc.identifier.uri.fl_str_mv http://hdl.handle.net/10362/105761
url http://hdl.handle.net/10362/105761
dc.language.iso.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv 1663-9812
PURE: 19979168
https://doi.org/10.3389/fphar.2020.01012
dc.rights.driver.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.source.none.fl_str_mv reponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação
instacron:RCAAP
instname_str Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação
instacron_str RCAAP
institution RCAAP
reponame_str Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
collection Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
repository.name.fl_str_mv Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação
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