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ResearchIn-Press PreviewNeuroscience Open Access | 10.1172/JCI162253

Complement C3a treatment accelerates recovery after stroke via modulation of astrocyte reactivity and cortical connectivity

Anna Stokowska,1 Markus Aswendt,2 Daniel Zucha,3 Stephanie Lohmann,1 Frederique Wieters,2 Javier Moran Suarez,1 Alison L. Atkins,1 YiXian Li,1 Maria Miteva,1 Julia Lewin,1 Dirk Wiedermann,4 Michael Diedenhofen,4 Åsa Torinsson Naluai,5 Pavel Abaffy,3 Lukas Valihrach,3 Mikael Kubista,3 Mathias Hoehn,6 Milos Pekny,7 and Marcela Pekna1

1Department of Clinical Neuroscience, Institute of Neuroscience and Physiology, University of Gothenburg, Gothenburg, Sweden

2Department of Neurology, University of Cologne, Cologne, Germany

3Laboratory of Gene Expression, Institute of Biotechnology, Czech Academy of Sciences, Vestec, Czech Republic

4Multimodal Imaging Group, Max Planck Institute for Metabolism Research, Cologne, Germany

5Department of Laboratory Medicine, Institute of Biomedicine, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden

6Cognitive Neuroscience, Institute of Neuroscience and Medicine (INM-3), Research Center Juelich, Cologne, Germany

7Department of Clinical Neuroscience and Rehabilitation, Institute of Biomedicine, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden

Find articles by Stokowska, A. in: PubMed | Google Scholar

1Department of Clinical Neuroscience, Institute of Neuroscience and Physiology, University of Gothenburg, Gothenburg, Sweden

2Department of Neurology, University of Cologne, Cologne, Germany

3Laboratory of Gene Expression, Institute of Biotechnology, Czech Academy of Sciences, Vestec, Czech Republic

4Multimodal Imaging Group, Max Planck Institute for Metabolism Research, Cologne, Germany

5Department of Laboratory Medicine, Institute of Biomedicine, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden

6Cognitive Neuroscience, Institute of Neuroscience and Medicine (INM-3), Research Center Juelich, Cologne, Germany

7Department of Clinical Neuroscience and Rehabilitation, Institute of Biomedicine, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden

Find articles by Aswendt, M. in: PubMed | Google Scholar |

1Department of Clinical Neuroscience, Institute of Neuroscience and Physiology, University of Gothenburg, Gothenburg, Sweden

2Department of Neurology, University of Cologne, Cologne, Germany

3Laboratory of Gene Expression, Institute of Biotechnology, Czech Academy of Sciences, Vestec, Czech Republic

4Multimodal Imaging Group, Max Planck Institute for Metabolism Research, Cologne, Germany

5Department of Laboratory Medicine, Institute of Biomedicine, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden

6Cognitive Neuroscience, Institute of Neuroscience and Medicine (INM-3), Research Center Juelich, Cologne, Germany

7Department of Clinical Neuroscience and Rehabilitation, Institute of Biomedicine, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden

Find articles by Zucha, D. in: PubMed | Google Scholar |

1Department of Clinical Neuroscience, Institute of Neuroscience and Physiology, University of Gothenburg, Gothenburg, Sweden

2Department of Neurology, University of Cologne, Cologne, Germany

3Laboratory of Gene Expression, Institute of Biotechnology, Czech Academy of Sciences, Vestec, Czech Republic

4Multimodal Imaging Group, Max Planck Institute for Metabolism Research, Cologne, Germany

5Department of Laboratory Medicine, Institute of Biomedicine, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden

6Cognitive Neuroscience, Institute of Neuroscience and Medicine (INM-3), Research Center Juelich, Cologne, Germany

7Department of Clinical Neuroscience and Rehabilitation, Institute of Biomedicine, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden

Find articles by Lohmann, S. in: PubMed | Google Scholar

1Department of Clinical Neuroscience, Institute of Neuroscience and Physiology, University of Gothenburg, Gothenburg, Sweden

2Department of Neurology, University of Cologne, Cologne, Germany

3Laboratory of Gene Expression, Institute of Biotechnology, Czech Academy of Sciences, Vestec, Czech Republic

4Multimodal Imaging Group, Max Planck Institute for Metabolism Research, Cologne, Germany

5Department of Laboratory Medicine, Institute of Biomedicine, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden

6Cognitive Neuroscience, Institute of Neuroscience and Medicine (INM-3), Research Center Juelich, Cologne, Germany

7Department of Clinical Neuroscience and Rehabilitation, Institute of Biomedicine, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden

Find articles by Wieters, F. in: PubMed | Google Scholar

1Department of Clinical Neuroscience, Institute of Neuroscience and Physiology, University of Gothenburg, Gothenburg, Sweden

2Department of Neurology, University of Cologne, Cologne, Germany

3Laboratory of Gene Expression, Institute of Biotechnology, Czech Academy of Sciences, Vestec, Czech Republic

4Multimodal Imaging Group, Max Planck Institute for Metabolism Research, Cologne, Germany

5Department of Laboratory Medicine, Institute of Biomedicine, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden

6Cognitive Neuroscience, Institute of Neuroscience and Medicine (INM-3), Research Center Juelich, Cologne, Germany

7Department of Clinical Neuroscience and Rehabilitation, Institute of Biomedicine, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden

Find articles by Moran Suarez, J. in: PubMed | Google Scholar

1Department of Clinical Neuroscience, Institute of Neuroscience and Physiology, University of Gothenburg, Gothenburg, Sweden

2Department of Neurology, University of Cologne, Cologne, Germany

3Laboratory of Gene Expression, Institute of Biotechnology, Czech Academy of Sciences, Vestec, Czech Republic

4Multimodal Imaging Group, Max Planck Institute for Metabolism Research, Cologne, Germany

5Department of Laboratory Medicine, Institute of Biomedicine, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden

6Cognitive Neuroscience, Institute of Neuroscience and Medicine (INM-3), Research Center Juelich, Cologne, Germany

7Department of Clinical Neuroscience and Rehabilitation, Institute of Biomedicine, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden

Find articles by Atkins, A. in: PubMed | Google Scholar

1Department of Clinical Neuroscience, Institute of Neuroscience and Physiology, University of Gothenburg, Gothenburg, Sweden

2Department of Neurology, University of Cologne, Cologne, Germany

3Laboratory of Gene Expression, Institute of Biotechnology, Czech Academy of Sciences, Vestec, Czech Republic

4Multimodal Imaging Group, Max Planck Institute for Metabolism Research, Cologne, Germany

5Department of Laboratory Medicine, Institute of Biomedicine, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden

6Cognitive Neuroscience, Institute of Neuroscience and Medicine (INM-3), Research Center Juelich, Cologne, Germany

7Department of Clinical Neuroscience and Rehabilitation, Institute of Biomedicine, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden

Find articles by Li, Y. in: PubMed | Google Scholar

1Department of Clinical Neuroscience, Institute of Neuroscience and Physiology, University of Gothenburg, Gothenburg, Sweden

2Department of Neurology, University of Cologne, Cologne, Germany

3Laboratory of Gene Expression, Institute of Biotechnology, Czech Academy of Sciences, Vestec, Czech Republic

4Multimodal Imaging Group, Max Planck Institute for Metabolism Research, Cologne, Germany

5Department of Laboratory Medicine, Institute of Biomedicine, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden

6Cognitive Neuroscience, Institute of Neuroscience and Medicine (INM-3), Research Center Juelich, Cologne, Germany

7Department of Clinical Neuroscience and Rehabilitation, Institute of Biomedicine, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden

Find articles by Miteva, M. in: PubMed | Google Scholar

1Department of Clinical Neuroscience, Institute of Neuroscience and Physiology, University of Gothenburg, Gothenburg, Sweden

2Department of Neurology, University of Cologne, Cologne, Germany

3Laboratory of Gene Expression, Institute of Biotechnology, Czech Academy of Sciences, Vestec, Czech Republic

4Multimodal Imaging Group, Max Planck Institute for Metabolism Research, Cologne, Germany

5Department of Laboratory Medicine, Institute of Biomedicine, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden

6Cognitive Neuroscience, Institute of Neuroscience and Medicine (INM-3), Research Center Juelich, Cologne, Germany

7Department of Clinical Neuroscience and Rehabilitation, Institute of Biomedicine, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden

Find articles by Lewin, J. in: PubMed | Google Scholar

1Department of Clinical Neuroscience, Institute of Neuroscience and Physiology, University of Gothenburg, Gothenburg, Sweden

2Department of Neurology, University of Cologne, Cologne, Germany

3Laboratory of Gene Expression, Institute of Biotechnology, Czech Academy of Sciences, Vestec, Czech Republic

4Multimodal Imaging Group, Max Planck Institute for Metabolism Research, Cologne, Germany

5Department of Laboratory Medicine, Institute of Biomedicine, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden

6Cognitive Neuroscience, Institute of Neuroscience and Medicine (INM-3), Research Center Juelich, Cologne, Germany

7Department of Clinical Neuroscience and Rehabilitation, Institute of Biomedicine, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden

Find articles by Wiedermann, D. in: PubMed | Google Scholar

1Department of Clinical Neuroscience, Institute of Neuroscience and Physiology, University of Gothenburg, Gothenburg, Sweden

2Department of Neurology, University of Cologne, Cologne, Germany

3Laboratory of Gene Expression, Institute of Biotechnology, Czech Academy of Sciences, Vestec, Czech Republic

4Multimodal Imaging Group, Max Planck Institute for Metabolism Research, Cologne, Germany

5Department of Laboratory Medicine, Institute of Biomedicine, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden

6Cognitive Neuroscience, Institute of Neuroscience and Medicine (INM-3), Research Center Juelich, Cologne, Germany

7Department of Clinical Neuroscience and Rehabilitation, Institute of Biomedicine, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden

Find articles by Diedenhofen, M. in: PubMed | Google Scholar

1Department of Clinical Neuroscience, Institute of Neuroscience and Physiology, University of Gothenburg, Gothenburg, Sweden

2Department of Neurology, University of Cologne, Cologne, Germany

3Laboratory of Gene Expression, Institute of Biotechnology, Czech Academy of Sciences, Vestec, Czech Republic

4Multimodal Imaging Group, Max Planck Institute for Metabolism Research, Cologne, Germany

5Department of Laboratory Medicine, Institute of Biomedicine, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden

6Cognitive Neuroscience, Institute of Neuroscience and Medicine (INM-3), Research Center Juelich, Cologne, Germany

7Department of Clinical Neuroscience and Rehabilitation, Institute of Biomedicine, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden

Find articles by Torinsson Naluai, Å. in: PubMed | Google Scholar |

1Department of Clinical Neuroscience, Institute of Neuroscience and Physiology, University of Gothenburg, Gothenburg, Sweden

2Department of Neurology, University of Cologne, Cologne, Germany

3Laboratory of Gene Expression, Institute of Biotechnology, Czech Academy of Sciences, Vestec, Czech Republic

4Multimodal Imaging Group, Max Planck Institute for Metabolism Research, Cologne, Germany

5Department of Laboratory Medicine, Institute of Biomedicine, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden

6Cognitive Neuroscience, Institute of Neuroscience and Medicine (INM-3), Research Center Juelich, Cologne, Germany

7Department of Clinical Neuroscience and Rehabilitation, Institute of Biomedicine, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden

Find articles by Abaffy, P. in: PubMed | Google Scholar |

1Department of Clinical Neuroscience, Institute of Neuroscience and Physiology, University of Gothenburg, Gothenburg, Sweden

2Department of Neurology, University of Cologne, Cologne, Germany

3Laboratory of Gene Expression, Institute of Biotechnology, Czech Academy of Sciences, Vestec, Czech Republic

4Multimodal Imaging Group, Max Planck Institute for Metabolism Research, Cologne, Germany

5Department of Laboratory Medicine, Institute of Biomedicine, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden

6Cognitive Neuroscience, Institute of Neuroscience and Medicine (INM-3), Research Center Juelich, Cologne, Germany

7Department of Clinical Neuroscience and Rehabilitation, Institute of Biomedicine, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden

Find articles by Valihrach, L. in: PubMed | Google Scholar |

1Department of Clinical Neuroscience, Institute of Neuroscience and Physiology, University of Gothenburg, Gothenburg, Sweden

2Department of Neurology, University of Cologne, Cologne, Germany

3Laboratory of Gene Expression, Institute of Biotechnology, Czech Academy of Sciences, Vestec, Czech Republic

4Multimodal Imaging Group, Max Planck Institute for Metabolism Research, Cologne, Germany

5Department of Laboratory Medicine, Institute of Biomedicine, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden

6Cognitive Neuroscience, Institute of Neuroscience and Medicine (INM-3), Research Center Juelich, Cologne, Germany

7Department of Clinical Neuroscience and Rehabilitation, Institute of Biomedicine, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden

Find articles by Kubista, M. in: PubMed | Google Scholar

1Department of Clinical Neuroscience, Institute of Neuroscience and Physiology, University of Gothenburg, Gothenburg, Sweden

2Department of Neurology, University of Cologne, Cologne, Germany

3Laboratory of Gene Expression, Institute of Biotechnology, Czech Academy of Sciences, Vestec, Czech Republic

4Multimodal Imaging Group, Max Planck Institute for Metabolism Research, Cologne, Germany

5Department of Laboratory Medicine, Institute of Biomedicine, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden

6Cognitive Neuroscience, Institute of Neuroscience and Medicine (INM-3), Research Center Juelich, Cologne, Germany

7Department of Clinical Neuroscience and Rehabilitation, Institute of Biomedicine, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden

Find articles by Hoehn, M. in: PubMed | Google Scholar

1Department of Clinical Neuroscience, Institute of Neuroscience and Physiology, University of Gothenburg, Gothenburg, Sweden

2Department of Neurology, University of Cologne, Cologne, Germany

3Laboratory of Gene Expression, Institute of Biotechnology, Czech Academy of Sciences, Vestec, Czech Republic

4Multimodal Imaging Group, Max Planck Institute for Metabolism Research, Cologne, Germany

5Department of Laboratory Medicine, Institute of Biomedicine, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden

6Cognitive Neuroscience, Institute of Neuroscience and Medicine (INM-3), Research Center Juelich, Cologne, Germany

7Department of Clinical Neuroscience and Rehabilitation, Institute of Biomedicine, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden

Find articles by Pekny, M. in: PubMed | Google Scholar

1Department of Clinical Neuroscience, Institute of Neuroscience and Physiology, University of Gothenburg, Gothenburg, Sweden

2Department of Neurology, University of Cologne, Cologne, Germany

3Laboratory of Gene Expression, Institute of Biotechnology, Czech Academy of Sciences, Vestec, Czech Republic

4Multimodal Imaging Group, Max Planck Institute for Metabolism Research, Cologne, Germany

5Department of Laboratory Medicine, Institute of Biomedicine, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden

6Cognitive Neuroscience, Institute of Neuroscience and Medicine (INM-3), Research Center Juelich, Cologne, Germany

7Department of Clinical Neuroscience and Rehabilitation, Institute of Biomedicine, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden

Find articles by Pekna, M. in: PubMed | Google Scholar |

Published March 30, 2023 - More info

J Clin Invest. https://doi.org/10.1172/JCI162253.
Copyright © 2023, Stokowska et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published March 30, 2023 - Version history
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Abstract

Despite advances in acute care, ischemic stroke remains a major cause of long-term disability. Approaches targeting both neuronal and glial responses are needed to enhance recovery and improve long-term outcome. The complement C3a receptor (C3aR) is a regulator of inflammation with roles in neurodevelopment, neural plasticity, and neurodegeneration. Using mice lacking C3aR (C3aR–/–) and mice overexpressing C3a in the brain, we uncovered two opposing effects of C3aR signaling on functional recovery after ischemic stroke: inhibition in the acute phase and facilitation in the later phase. Peri-infarct astrocyte reactivity was increased and density of microglia reduced in C3aR–/– mice, C3a overexpression led to the opposite effects. Pharmacological treatment of wild-type mice with intranasal C3a starting 7 days after stroke accelerated recovery of motor function and attenuated astrocyte reactivity without enhancing microgliosis. C3a treatment stimulated global white matter reorganization, increased peri-infarct structural connectivity and upregulated Igf1 and Thbs4 in the peri-infarct cortex. Thus, C3a treatment from day 7 after stroke exerts positive effects on astrocytes and neuronal connectivity while avoiding the deleterious consequences of C3aR signaling during the acute phase. Intranasal administration of C3aR agonists within convenient time window holds translational promise to improve outcome after ischemic stroke.

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  • Version 1 (March 30, 2023): In-Press Preview
  • Version 2 (May 15, 2023): Electronic publication
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