Microglia Susceptibility to Free Bilirubin Is Age-Dependent
| العنوان: | Microglia Susceptibility to Free Bilirubin Is Age-Dependent |
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| المؤلفون: | Ana Rita Vaz, Ana Sofia Falcão, Eleonora Scarpa, Carlotta Semproni, Dora Brites |
| المساهمون: | Centro de Estudos de Doenças Crónicas (CEDOC), NOVA Medical School|Faculdade de Ciências Médicas (NMS|FCM) |
| المصدر: | Frontiers in Pharmacology, Vol 11 (2020) Frontiers in Pharmacology Repositório Científico de Acesso Aberto de Portugal Repositório Científico de Acesso Aberto de Portugal (RCAAP) instacron:RCAAP |
| بيانات النشر: | Frontiers Media S.A., 2020. |
| سنة النشر: | 2020 |
| مصطلحات موضوعية: | 0301 basic medicine, CD1, pro- and anti-inflammatory markers, Andrology, 03 medical and health sciences, 0302 clinical medicine, CX3CR1, medicine, unconjugated bilirubin, microglia inflammatory response, Pharmacology (medical), Original Research, Pharmacology, young and aged cultured microglia, Microglia, biology, Chemistry, lcsh:RM1-950, Neurotoxicity, medicine.disease, Oligodendrocyte, Arginase, 030104 developmental biology, medicine.anatomical_structure, lcsh:Therapeutics. Pharmacology, Integrin alpha M, nervous system, Apoptosis, 030220 oncology & carcinogenesis, biology.protein, inflammatory-miRNAs |
| الوصف: | 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 Increased 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. publishersversion published |
| اللغة: | English |
| تدمد: | 1663-9812 2015-2019 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::0acb4886dd78849cff2daa2237db0c9b https://www.frontiersin.org/article/10.3389/fphar.2020.01012/full |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi.dedup.....0acb4886dd78849cff2daa2237db0c9b |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 16639812 20152019 |
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