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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Frontiers Media S.A.
2021-12-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2021.768198/full |
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| author | Andrea Pozo-Rodrigálvarez YiXian Li Anna Stokowska Jingyun Wu Jingyun Wu Verena Dehm Hana Sourkova Harry Steinbusch Harry Steinbusch Carina Mallard Henrik Hagberg Henrik Hagberg Milos Pekny Marcela Pekna |
| author_facet | Andrea Pozo-Rodrigálvarez YiXian Li Anna Stokowska Jingyun Wu Jingyun Wu Verena Dehm Hana Sourkova Harry Steinbusch Harry Steinbusch Carina Mallard Henrik Hagberg Henrik Hagberg Milos Pekny Marcela Pekna |
| author_sort | Andrea Pozo-Rodrigálvarez |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-12-13T18:55:23Z |
| format | Article |
| id | doaj.art-7eaffa3174164f069d43137e2db8505b |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-12-13T18:55:23Z |
| publishDate | 2021-12-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-7eaffa3174164f069d43137e2db8505b2022-12-21T23:34:49ZengFrontiers Media S.A.Frontiers in Immunology1664-32242021-12-011210.3389/fimmu.2021.768198768198C3a Receptor Signaling Inhibits Neurodegeneration Induced by Neonatal Hypoxic-Ischemic Brain InjuryAndrea Pozo-Rodrigálvarez0YiXian Li1Anna Stokowska2Jingyun Wu3Jingyun Wu4Verena Dehm5Hana Sourkova6Harry Steinbusch7Harry Steinbusch8Carina Mallard9Henrik Hagberg10Henrik Hagberg11Milos Pekny12Marcela Pekna13Laboratory of Regenerative Neuroimmunology, Center for Brain Repair, Department of Clinical Neuroscience, Institute of Neuroscience and Physiology, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, SwedenLaboratory of Regenerative Neuroimmunology, Center for Brain Repair, Department of Clinical Neuroscience, Institute of Neuroscience and Physiology, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, SwedenLaboratory of Regenerative Neuroimmunology, Center for Brain Repair, Department of Clinical Neuroscience, Institute of Neuroscience and Physiology, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, SwedenLaboratory of Regenerative Neuroimmunology, Center for Brain Repair, Department of Clinical Neuroscience, Institute of Neuroscience and Physiology, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, SwedenLaboratory of Astrocyte Biology and CNS Regeneration, Center for Brain Repair, Department of Clinical Neuroscience, Institute of Neuroscience and Physiology, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, SwedenLaboratory of Regenerative Neuroimmunology, Center for Brain Repair, Department of Clinical Neuroscience, Institute of Neuroscience and Physiology, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, SwedenLaboratory of Astrocyte Biology and CNS Regeneration, Center for Brain Repair, Department of Clinical Neuroscience, Institute of Neuroscience and Physiology, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, SwedenDepartment of Neuroscience, Faculty of Health, Medicine and Life Sciences, Maastricht University, Maastrich, NetherlandsDepartment of Brain & Cognitive Sciences, Daegu Gyeongbuk Institute of Science and Technology (DGIST), Daegu, South KoreaCentre of Perinatal Medicine & Health, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, SwedenCentre of Perinatal Medicine & Health, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, SwedenCentre for the Developing Brain, King’s College, London, United KingdomLaboratory of Astrocyte Biology and CNS Regeneration, Center for Brain Repair, Department of Clinical Neuroscience, Institute of Neuroscience and Physiology, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, SwedenLaboratory of Regenerative Neuroimmunology, Center for Brain Repair, Department of Clinical Neuroscience, Institute of Neuroscience and Physiology, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, SwedenHypoxic-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.https://www.frontiersin.org/articles/10.3389/fimmu.2021.768198/fulldeveloping brainneonatal encephalopathyhypoxia-ischemiacomplement system: neurodegenerationreactive gliosis |
| spellingShingle | Andrea Pozo-Rodrigálvarez YiXian Li Anna Stokowska Jingyun Wu Jingyun Wu Verena Dehm Hana Sourkova Harry Steinbusch Harry Steinbusch Carina Mallard Henrik Hagberg Henrik Hagberg Milos Pekny Marcela Pekna C3a Receptor Signaling Inhibits Neurodegeneration Induced by Neonatal Hypoxic-Ischemic Brain Injury Frontiers in Immunology developing brain neonatal encephalopathy hypoxia-ischemia complement system: neurodegeneration reactive gliosis |
| 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 | developing brain neonatal encephalopathy hypoxia-ischemia complement system: neurodegeneration reactive gliosis |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2021.768198/full |
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