Otxoa-de-Amezaga, Amaia and Miró-Mur, Francesc and Pedragosa, Jordi and Gallizioli, Mattia and Justicia, Carles and Gaja‑Capdevila, Núria and Ruíz‑Jaen, Francisca and Salas‑Perdomo, Angélica and Bosch, Anna and Calvo, Maria and Márquez‑Kisinousky, Leonardo and Dénes, Ádám and Gunzer, Matthias and Planas, Anna M. (2019) Microglial cell loss after ischemic stroke favors brain neutrophil accumulation. Acta Neuropathologica, 137 (2). pp. 321-341. ISSN 0001-6322
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Microglialcelllossafterischemicstrokefavorsbrainneutrophil.pdf Restricted to Repository staff only Download (5MB) |
Official URL: https://doi.org/10.1007/s00401-018-1954-4
Abstract
Stroke attracts neutrophils to the injured brain tissue where they can damage the integrity of the blood-brain barrier and exacerbate the lesion. However, the mechanisms involved in neutrophil transmigration, location and accumulation in the ischemic brain are not fully elucidated. Neutrophils can reach the perivascular spaces of brain vessels after crossing the endothelial cell layer and endothelial basal lamina of post-capillary venules, or migrating from the leptomeninges following pial vessel extravasation and/or a suggested translocation from the skull bone marrow. Based on previous observations of microglia phagocytosing neutrophils recruited to the ischemic brain lesion, we hypothesized that microglial cells might control neutrophil accumulation in the injured brain. We studied a model of permanent occlusion of the middle cerebral artery in mice, including microglia- and neutrophil-reporter mice. Using various in vitro and in vivo strategies to impair microglial function or to eliminate microglia by targeting colony stimulating factor 1 receptor (CSF1R), this study demonstrates that microglial phagocytosis of neutrophils has fundamental consequences for the ischemic tissue. We found that reactive microglia engulf neutrophils at the periphery of the ischemic lesion, whereas local microglial cell loss and dystrophy occurring in the ischemic core are associated with the accumulation of neutrophils first in perivascular spaces and later in the parenchyma. Accordingly, microglia depletion by long-term treatment with a CSF1R inhibitor increased the numbers of neutrophils and enlarged the ischemic lesion. Hence, microglial phagocytic function sets a critical line of defense against the vascular and tissue damaging capacity of neutrophils in brain ischemia.
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| Additional Information: | Export Date: 5 May 2019 Department of Brain Ischemia and Neurodegeneration, Institut d’Investigacions Biomèdiques de Barcelona (IIBB)-Consejo Superior de Investigaciones Científicas (CSIC), Rossello 161 planta 6, Barcelona, 08036, Spain Area of Neuroscience, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain Scientific and Technological Centers, Universitat de Barcelona (CCiTUB) Campus Medicina Clínic, Barcelona, Spain Laboratory of Neuroimmunology, Institute of Experimental Medicine, Hungarian Academy of Sciences, Budapest, Hungary Institute for Experimental Immunology and Imaging, University Hospital, University Duisburg-Essen, Essen, Germany Cited By :1 Export Date: 17 July 2019 CODEN: ANPTA Correspondence Address: Planas, A.M.; Department of Brain Ischemia and Neurodegeneration, Institut d’Investigacions Biomèdiques de Barcelona (IIBB)-Consejo Superior de Investigaciones Científicas (CSIC), Rossello 161 planta 6, Spain; email: anna.planas@iibb.csic.es Chemicals/CAS: colony stimulating factor 1, 81627-83-0 Tradenames: gw 2580 Funding details: Generalitat de Catalunya Funding details: Ministerio de Economía y Competitividad, SAF2017-87459-R, SAF2014-56279-R Funding text 1: Acknowledgements AOdA had a predoctoral fellowship from the MINECO-FPI program and FMM had a PERIS award by the Health Department of Generalitat de Catalunya. Part of this work was performed at the Centre de Recerca Biomèdica Cellex, Barcelona. The CERCA Programme of Generalitat de Catalunya supports the Insti-tut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS). PLX5622 was provided by Plexxikon under Materials Transfer Agreement. We acknowledge the Cytomics and Image Platforms of IDIBAPS for access to equipment. We would like to thank Elisenda Coll (Advanced Optical Microscopy-CCiTUB) for excellent technical assistance. We thank the Neurological Tissue Bank of the Biobank-Hospital Clinic-IDIBAPS for sample and data procurement, and to patient’s relatives for giving consent to sample use for research purposes. Funding text 2: Funding Supported by grants of the Ministerio de Economía y Com-petitividad (MINECO) (SAF2014-56279-R and SAF2017-87459-R). Department of Brain Ischemia and Neurodegeneration, Institut d’Investigacions Biomèdiques de Barcelona (IIBB)-Consejo Superior de Investigaciones Científicas (CSIC), Rossello 161 planta 6, Barcelona, 08036, Spain Area of Neuroscience, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain Scientific and Technological Centers, Universitat de Barcelona (CCiTUB) Campus Medicina Clínic, Barcelona, Spain Laboratory of Neuroimmunology, Institute of Experimental Medicine, Hungarian Academy of Sciences, Budapest, Hungary Institute for Experimental Immunology and Imaging, University Hospital, University Duisburg-Essen, Essen, Germany Cited By :2 Export Date: 19 July 2019 CODEN: ANPTA Correspondence Address: Planas, A.M.; Department of Brain Ischemia and Neurodegeneration, Institut d’Investigacions Biomèdiques de Barcelona (IIBB)-Consejo Superior de Investigaciones Científicas (CSIC), Rossello 161 planta 6, Spain; email: anna.planas@iibb.csic.es Chemicals/CAS: colony stimulating factor 1, 81627-83-0 Tradenames: gw 2580 Funding details: Generalitat de Catalunya Funding details: Ministerio de Economía y Competitividad, SAF2017-87459-R, SAF2014-56279-R Funding text 1: Acknowledgements AOdA had a predoctoral fellowship from the MINECO-FPI program and FMM had a PERIS award by the Health Department of Generalitat de Catalunya. Part of this work was performed at the Centre de Recerca Biomèdica Cellex, Barcelona. The CERCA Programme of Generalitat de Catalunya supports the Insti-tut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS). PLX5622 was provided by Plexxikon under Materials Transfer Agreement. We acknowledge the Cytomics and Image Platforms of IDIBAPS for access to equipment. We would like to thank Elisenda Coll (Advanced Optical Microscopy-CCiTUB) for excellent technical assistance. We thank the Neurological Tissue Bank of the Biobank-Hospital Clinic-IDIBAPS for sample and data procurement, and to patient’s relatives for giving consent to sample use for research purposes. Funding text 2: Funding Supported by grants of the Ministerio de Economía y Com-petitividad (MINECO) (SAF2014-56279-R and SAF2017-87459-R). Department of Brain Ischemia and Neurodegeneration, Institut d’Investigacions Biomèdiques de Barcelona (IIBB)-Consejo Superior de Investigaciones Científicas (CSIC), Rossello 161 planta 6, Barcelona, 08036, Spain Area of Neuroscience, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain Scientific and Technological Centers, Universitat de Barcelona (CCiTUB) Campus Medicina Clínic, Barcelona, Spain Laboratory of Neuroimmunology, Institute of Experimental Medicine, Hungarian Academy of Sciences, Budapest, Hungary Institute for Experimental Immunology and Imaging, University Hospital, University Duisburg-Essen, Essen, Germany Cited By :2 Export Date: 22 July 2019 CODEN: ANPTA Correspondence Address: Planas, A.M.; Department of Brain Ischemia and Neurodegeneration, Institut d’Investigacions Biomèdiques de Barcelona (IIBB)-Consejo Superior de Investigaciones Científicas (CSIC), Rossello 161 planta 6, Spain; email: anna.planas@iibb.csic.es Chemicals/CAS: colony stimulating factor 1, 81627-83-0 Tradenames: gw 2580 Funding details: Generalitat de Catalunya Funding details: Ministerio de Economía y Competitividad, SAF2017-87459-R, SAF2014-56279-R Funding text 1: Acknowledgements AOdA had a predoctoral fellowship from the MINECO-FPI program and FMM had a PERIS award by the Health Department of Generalitat de Catalunya. Part of this work was performed at the Centre de Recerca Biomèdica Cellex, Barcelona. The CERCA Programme of Generalitat de Catalunya supports the Insti-tut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS). PLX5622 was provided by Plexxikon under Materials Transfer Agreement. We acknowledge the Cytomics and Image Platforms of IDIBAPS for access to equipment. We would like to thank Elisenda Coll (Advanced Optical Microscopy-CCiTUB) for excellent technical assistance. We thank the Neurological Tissue Bank of the Biobank-Hospital Clinic-IDIBAPS for sample and data procurement, and to patient’s relatives for giving consent to sample use for research purposes. Funding text 2: Funding Supported by grants of the Ministerio de Economía y Com-petitividad (MINECO) (SAF2014-56279-R and SAF2017-87459-R). Department of Brain Ischemia and Neurodegeneration, Institut d’Investigacions Biomèdiques de Barcelona (IIBB)-Consejo Superior de Investigaciones Científicas (CSIC), Rossello 161 planta 6, Barcelona, 08036, Spain Area of Neuroscience, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain Scientific and Technological Centers, Universitat de Barcelona (CCiTUB) Campus Medicina Clínic, Barcelona, Spain Laboratory of Neuroimmunology, Institute of Experimental Medicine, Hungarian Academy of Sciences, Budapest, Hungary Institute for Experimental Immunology and Imaging, University Hospital, University Duisburg-Essen, Essen, Germany Cited By :2 Export Date: 27 July 2019 CODEN: ANPTA Correspondence Address: Planas, A.M.; Department of Brain Ischemia and Neurodegeneration, Institut d’Investigacions Biomèdiques de Barcelona (IIBB)-Consejo Superior de Investigaciones Científicas (CSIC), Rossello 161 planta 6, Spain; email: anna.planas@iibb.csic.es Chemicals/CAS: colony stimulating factor 1, 81627-83-0 Tradenames: gw 2580 Funding details: Generalitat de Catalunya Funding details: Ministerio de Economía y Competitividad, SAF2017-87459-R, SAF2014-56279-R Funding text 1: Acknowledgements AOdA had a predoctoral fellowship from the MINECO-FPI program and FMM had a PERIS award by the Health Department of Generalitat de Catalunya. Part of this work was performed at the Centre de Recerca Biomèdica Cellex, Barcelona. The CERCA Programme of Generalitat de Catalunya supports the Insti-tut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS). PLX5622 was provided by Plexxikon under Materials Transfer Agreement. We acknowledge the Cytomics and Image Platforms of IDIBAPS for access to equipment. We would like to thank Elisenda Coll (Advanced Optical Microscopy-CCiTUB) for excellent technical assistance. We thank the Neurological Tissue Bank of the Biobank-Hospital Clinic-IDIBAPS for sample and data procurement, and to patient’s relatives for giving consent to sample use for research purposes. Funding text 2: Funding Supported by grants of the Ministerio de Economía y Com-petitividad (MINECO) (SAF2014-56279-R and SAF2017-87459-R). Department of Brain Ischemia and Neurodegeneration, Institut d’Investigacions Biomèdiques de Barcelona (IIBB)-Consejo Superior de Investigaciones Científicas (CSIC), Rossello 161 planta 6, Barcelona, 08036, Spain Area of Neuroscience, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain Scientific and Technological Centers, Universitat de Barcelona (CCiTUB) Campus Medicina Clínic, Barcelona, Spain Laboratory of Neuroimmunology, Institute of Experimental Medicine, Hungarian Academy of Sciences, Budapest, Hungary Institute for Experimental Immunology and Imaging, University Hospital, University Duisburg-Essen, Essen, Germany Cited By :2 Export Date: 27 August 2019 CODEN: ANPTA Correspondence Address: Planas, A.M.; Department of Brain Ischemia and Neurodegeneration, Institut d’Investigacions Biomèdiques de Barcelona (IIBB)-Consejo Superior de Investigaciones Científicas (CSIC), Rossello 161 planta 6, Spain; email: anna.planas@iibb.csic.es Chemicals/CAS: colony stimulating factor 1, 81627-83-0 Tradenames: gw 2580 Funding details: Generalitat de Catalunya Funding details: Ministerio de Economía y Competitividad, SAF2017-87459-R, SAF2014-56279-R Funding text 1: Acknowledgements AOdA had a predoctoral fellowship from the MINECO-FPI program and FMM had a PERIS award by the Health Department of Generalitat de Catalunya. Part of this work was performed at the Centre de Recerca Biomèdica Cellex, Barcelona. The CERCA Programme of Generalitat de Catalunya supports the Insti-tut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS). PLX5622 was provided by Plexxikon under Materials Transfer Agreement. We acknowledge the Cytomics and Image Platforms of IDIBAPS for access to equipment. We would like to thank Elisenda Coll (Advanced Optical Microscopy-CCiTUB) for excellent technical assistance. We thank the Neurological Tissue Bank of the Biobank-Hospital Clinic-IDIBAPS for sample and data procurement, and to patient’s relatives for giving consent to sample use for research purposes. Funding text 2: Funding Supported by grants of the Ministerio de Economía y Com-petitividad (MINECO) (SAF2014-56279-R and SAF2017-87459-R). |
| Uncontrolled Keywords: | PHAGOCYTOSIS; MOUSE; human; brain ischemia; NEUTROPHILS; microglia; Colony stimulating factor 1 receptor; |
| Subjects: | R Medicine / orvostudomány > R1 Medicine (General) / orvostudomány általában |
| SWORD Depositor: | MTMT SWORD |
| Depositing User: | MTMT SWORD |
| Date Deposited: | 28 Nov 2019 10:11 |
| Last Modified: | 28 Nov 2019 10:11 |
| URI: | http://real.mtak.hu/id/eprint/103945 |
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