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The Cerebrospinal Fluid Inflammatory Response to Preterm Birth

Background: Preterm birth is the leading risk factor for perinatal white matter injury, which can lead to motor and neuropsychiatric impairment across the life course. There is an unmet clinical need for therapeutics. White matter injury is associated with an altered inflammatory response in the bra...

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Autores principales: Boardman, James P., Ireland, Graeme, Sullivan, Gemma, Pataky, Rozalia, Fleiss, Bobbi, Gressens, Pierre, Miron, Veronique
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6144928/
https://www.ncbi.nlm.nih.gov/pubmed/30258368
http://dx.doi.org/10.3389/fphys.2018.01299
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author Boardman, James P.
Ireland, Graeme
Sullivan, Gemma
Pataky, Rozalia
Fleiss, Bobbi
Gressens, Pierre
Miron, Veronique
author_facet Boardman, James P.
Ireland, Graeme
Sullivan, Gemma
Pataky, Rozalia
Fleiss, Bobbi
Gressens, Pierre
Miron, Veronique
author_sort Boardman, James P.
collection PubMed
description Background: Preterm birth is the leading risk factor for perinatal white matter injury, which can lead to motor and neuropsychiatric impairment across the life course. There is an unmet clinical need for therapeutics. White matter injury is associated with an altered inflammatory response in the brain, primarily led by microglia, and subsequent hypomyelination. However, microglia can release both damaging and trophic factors in response to injury, and a comprehensive assessment of these factors in the preterm central nervous system (CNS) has not been carried out. Method: A custom antibody array was used to assess relative levels of 50 inflammation- and myelination-associated proteins in the cerebrospinal fluid (CSF) of preterm infants in comparison to term controls. Results: Fifteen proteins differed between the groups: BDNF, BTC, C5a, FasL, Follistatin, IL-1β, IL-2, IL-4, IL-9, IL-17A, MIP-1α, MMP8, SPP1, TGFβ, and TNFβ (p < 0.05). To investigate the temporal regulation of these proteins after injury, we mined a gene expression dataset of microglia isolated from a mouse model of developmental white matter injury. Microglia in the experimental model showed dynamic temporal expression of genes encoding these proteins, with an initial and sustained pro-inflammatory response followed by a delayed anti-inflammatory response, and a continuous expression of genes predicted to inhibit healthy myelination. Conclusion: Preterm CSF shows a distinct neuroinflammatory profile compared to term controls, suggestive of a complex neural environment with concurrent damaging and reparative signals. We propose that limitation of pro-inflammatory responses, which occur early after perinatal insult, may prevent expression of myelination-suppressive genes and support healthy white matter development.
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spelling pubmed-61449282018-09-26 The Cerebrospinal Fluid Inflammatory Response to Preterm Birth Boardman, James P. Ireland, Graeme Sullivan, Gemma Pataky, Rozalia Fleiss, Bobbi Gressens, Pierre Miron, Veronique Front Physiol Physiology Background: Preterm birth is the leading risk factor for perinatal white matter injury, which can lead to motor and neuropsychiatric impairment across the life course. There is an unmet clinical need for therapeutics. White matter injury is associated with an altered inflammatory response in the brain, primarily led by microglia, and subsequent hypomyelination. However, microglia can release both damaging and trophic factors in response to injury, and a comprehensive assessment of these factors in the preterm central nervous system (CNS) has not been carried out. Method: A custom antibody array was used to assess relative levels of 50 inflammation- and myelination-associated proteins in the cerebrospinal fluid (CSF) of preterm infants in comparison to term controls. Results: Fifteen proteins differed between the groups: BDNF, BTC, C5a, FasL, Follistatin, IL-1β, IL-2, IL-4, IL-9, IL-17A, MIP-1α, MMP8, SPP1, TGFβ, and TNFβ (p < 0.05). To investigate the temporal regulation of these proteins after injury, we mined a gene expression dataset of microglia isolated from a mouse model of developmental white matter injury. Microglia in the experimental model showed dynamic temporal expression of genes encoding these proteins, with an initial and sustained pro-inflammatory response followed by a delayed anti-inflammatory response, and a continuous expression of genes predicted to inhibit healthy myelination. Conclusion: Preterm CSF shows a distinct neuroinflammatory profile compared to term controls, suggestive of a complex neural environment with concurrent damaging and reparative signals. We propose that limitation of pro-inflammatory responses, which occur early after perinatal insult, may prevent expression of myelination-suppressive genes and support healthy white matter development. Frontiers Media S.A. 2018-09-12 /pmc/articles/PMC6144928/ /pubmed/30258368 http://dx.doi.org/10.3389/fphys.2018.01299 Text en Copyright © 2018 Boardman, Ireland, Sullivan, Pataky, Fleiss, Gressens and Miron. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Physiology
Boardman, James P.
Ireland, Graeme
Sullivan, Gemma
Pataky, Rozalia
Fleiss, Bobbi
Gressens, Pierre
Miron, Veronique
The Cerebrospinal Fluid Inflammatory Response to Preterm Birth
title The Cerebrospinal Fluid Inflammatory Response to Preterm Birth
title_full The Cerebrospinal Fluid Inflammatory Response to Preterm Birth
title_fullStr The Cerebrospinal Fluid Inflammatory Response to Preterm Birth
title_full_unstemmed The Cerebrospinal Fluid Inflammatory Response to Preterm Birth
title_short The Cerebrospinal Fluid Inflammatory Response to Preterm Birth
title_sort cerebrospinal fluid inflammatory response to preterm birth
topic Physiology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6144928/
https://www.ncbi.nlm.nih.gov/pubmed/30258368
http://dx.doi.org/10.3389/fphys.2018.01299
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