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C3a Receptor Signaling Inhibits Neurodegeneration Induced by Neonatal Hypoxic-Ischemic Brain Injury

Hypoxic-ischemic neonatal encephalopathy due to perinatal asphyxia is the leading cause of brain injury in newborns. Clinical data suggest that brain inflammation induced by perinatal insults can persist for years. We previously showed that signaling through the receptor for complement peptide C3a (...

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Autores principales: Pozo-Rodrigálvarez, Andrea, Li, YiXian, Stokowska, Anna, Wu, Jingyun, Dehm, Verena, Sourkova, Hana, Steinbusch, Harry, Mallard, Carina, Hagberg, Henrik, Pekny, Milos, Pekna, Marcela
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8718687/
https://www.ncbi.nlm.nih.gov/pubmed/34975856
http://dx.doi.org/10.3389/fimmu.2021.768198
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author Pozo-Rodrigálvarez, Andrea
Li, YiXian
Stokowska, Anna
Wu, Jingyun
Dehm, Verena
Sourkova, Hana
Steinbusch, Harry
Mallard, Carina
Hagberg, Henrik
Pekny, Milos
Pekna, Marcela
author_facet Pozo-Rodrigálvarez, Andrea
Li, YiXian
Stokowska, Anna
Wu, Jingyun
Dehm, Verena
Sourkova, Hana
Steinbusch, Harry
Mallard, Carina
Hagberg, Henrik
Pekny, Milos
Pekna, Marcela
author_sort Pozo-Rodrigálvarez, Andrea
collection PubMed
description Hypoxic-ischemic neonatal encephalopathy due to perinatal asphyxia is the leading cause of brain injury in newborns. Clinical data suggest that brain inflammation induced by perinatal insults can persist for years. We previously showed that signaling through the receptor for complement peptide C3a (C3aR) protects against cognitive impairment induced by experimental perinatal asphyxia. To investigate the long-term neuropathological effects of hypoxic-ischemic injury to the developing brain and the role of C3aR signaling therein, we subjected wildtype mice, C3aR deficient mice, and mice expressing biologically active C3a in the CNS to mild hypoxic-ischemic brain injury on postnatal day 9. We found that such injury triggers neurodegeneration and pronounced reactive gliosis in the ipsilesional hippocampus both of which persist long into adulthood. Transgenic expression of C3a in reactive astrocytes reduced hippocampal neurodegeneration and reactive gliosis. In contrast, neurodegeneration and microglial cell density increased in mice lacking C3aR. Intranasal administration of C3a for 3 days starting 1 h after induction of hypoxia-ischemia reduced neurodegeneration and reactive gliosis in the hippocampus of wildtype mice. We conclude that neonatal hypoxic-ischemic brain injury leads to long-lasting neurodegeneration. This neurodegeneration is substantially reduced by treatment with C3aR agonists, conceivably through modulation of reactive gliosis.
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spelling pubmed-87186872022-01-01 C3a Receptor Signaling Inhibits Neurodegeneration Induced by Neonatal Hypoxic-Ischemic Brain Injury Pozo-Rodrigálvarez, Andrea Li, YiXian Stokowska, Anna Wu, Jingyun Dehm, Verena Sourkova, Hana Steinbusch, Harry Mallard, Carina Hagberg, Henrik Pekny, Milos Pekna, Marcela Front Immunol Immunology Hypoxic-ischemic neonatal encephalopathy due to perinatal asphyxia is the leading cause of brain injury in newborns. Clinical data suggest that brain inflammation induced by perinatal insults can persist for years. We previously showed that signaling through the receptor for complement peptide C3a (C3aR) protects against cognitive impairment induced by experimental perinatal asphyxia. To investigate the long-term neuropathological effects of hypoxic-ischemic injury to the developing brain and the role of C3aR signaling therein, we subjected wildtype mice, C3aR deficient mice, and mice expressing biologically active C3a in the CNS to mild hypoxic-ischemic brain injury on postnatal day 9. We found that such injury triggers neurodegeneration and pronounced reactive gliosis in the ipsilesional hippocampus both of which persist long into adulthood. Transgenic expression of C3a in reactive astrocytes reduced hippocampal neurodegeneration and reactive gliosis. In contrast, neurodegeneration and microglial cell density increased in mice lacking C3aR. Intranasal administration of C3a for 3 days starting 1 h after induction of hypoxia-ischemia reduced neurodegeneration and reactive gliosis in the hippocampus of wildtype mice. We conclude that neonatal hypoxic-ischemic brain injury leads to long-lasting neurodegeneration. This neurodegeneration is substantially reduced by treatment with C3aR agonists, conceivably through modulation of reactive gliosis. Frontiers Media S.A. 2021-12-17 /pmc/articles/PMC8718687/ /pubmed/34975856 http://dx.doi.org/10.3389/fimmu.2021.768198 Text en Copyright © 2021 Pozo-Rodrigálvarez, Li, Stokowska, Wu, Dehm, Sourkova, Steinbusch, Mallard, Hagberg, Pekny and Pekna https://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 Immunology
Pozo-Rodrigálvarez, Andrea
Li, YiXian
Stokowska, Anna
Wu, Jingyun
Dehm, Verena
Sourkova, Hana
Steinbusch, Harry
Mallard, Carina
Hagberg, Henrik
Pekny, Milos
Pekna, Marcela
C3a Receptor Signaling Inhibits Neurodegeneration Induced by Neonatal Hypoxic-Ischemic Brain Injury
title C3a Receptor Signaling Inhibits Neurodegeneration Induced by Neonatal Hypoxic-Ischemic Brain Injury
title_full C3a Receptor Signaling Inhibits Neurodegeneration Induced by Neonatal Hypoxic-Ischemic Brain Injury
title_fullStr C3a Receptor Signaling Inhibits Neurodegeneration Induced by Neonatal Hypoxic-Ischemic Brain Injury
title_full_unstemmed C3a Receptor Signaling Inhibits Neurodegeneration Induced by Neonatal Hypoxic-Ischemic Brain Injury
title_short C3a Receptor Signaling Inhibits Neurodegeneration Induced by Neonatal Hypoxic-Ischemic Brain Injury
title_sort c3a receptor signaling inhibits neurodegeneration induced by neonatal hypoxic-ischemic brain injury
topic Immunology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8718687/
https://www.ncbi.nlm.nih.gov/pubmed/34975856
http://dx.doi.org/10.3389/fimmu.2021.768198
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