title: Interfering with the Chronic Immune Response Rescues Chronic Degeneration After Traumatic Brain Injury.
abstract: After traumatic brain injury (TBI), neurons surviving the initial insult can undergo chronic (secondary) degeneration via poorly understood mechanisms, resulting in long-term cognitive impairment. Although a neuroinflammatory response is promptly activated after TBI, it is unknown whether it has a significant role in chronic phases of TBI (>1 year after injury). Using a closed-head injury model of TBI in mice, we showed by MRI scans that TBI caused substantial degeneration at the lesion site within a few weeks and these did not expand significantly thereafter. However, chronic alterations in neurons were observed, with reduced dendritic spine density lasting >1 year after injury. In parallel, we found a long-lasting inflammatory response throughout the entire brain. Deletion of one allele of CX3CR1, a chemokine receptor, limited infiltration of peripheral immune cells and largely prevented the chronic degeneration of the injured brain and provided a better functional recovery in female, but not male, mice. Therefore, targeting persistent neuroinflammation presents a new therapeutic option to reduce chronic neurodegeneration.
  
  
  
  Traumatic brain injury (TBI) often causes chronic neurological problems including epilepsy, neuropsychiatric disorders, and dementia through unknown mechanisms. Our study demonstrates that inflammatory cells invading the brain lead to secondary brain damage. Sex-specific amelioration of chronic neuroinflammation rescues the brain degeneration and results in improved motor functions. Therefore, this study pinpoints an effective therapeutic approach to preventing secondary complications after TBI.
authors.affiliation: Institute for Stroke and Dementia Research, Klinikum der Universität München, Ludwig Maximilian University of Munich, 81377 Munich, Germany, Munich Cluster for Systems Neurology (SyNergy), 81377 Munich, Germany, Graduate School of Neuroscience Munich, 82152 Planegg-Martinsried, Germany, and Department of Neuroscience, Genentech, Inc., South San Francisco, California 94080 Ali.Ertuerk@med.uni-muenchen.de.
authors.forename: Ali
authors.identifier: 0000-0001-5163-5100
authors.initials: A
authors.lastname: Ertürk
authors.affiliation: Institute for Stroke and Dementia Research, Klinikum der Universität München, Ludwig Maximilian University of Munich, 81377 Munich, Germany.
authors.forename: Susanne
authors.initials: S
authors.lastname: Mentz
authors.affiliation: Department of Neuroscience, Genentech, Inc., South San Francisco, California 94080.
authors.forename: Erik E
authors.initials: EE
authors.lastname: Stout
authors.affiliation: Department of Neuroscience, Genentech, Inc., South San Francisco, California 94080.
authors.forename: Maj
authors.initials: M
authors.lastname: Hedehus
authors.affiliation: Department of Neuroscience, Genentech, Inc., South San Francisco, California 94080.
authors.forename: Sara L
authors.initials: SL
authors.lastname: Dominguez
authors.affiliation: Institute for Stroke and Dementia Research, Klinikum der Universität München, Ludwig Maximilian University of Munich, 81377 Munich, Germany.
authors.forename: Lisa
authors.initials: L
authors.lastname: Neumaier
authors.affiliation: Institute for Stroke and Dementia Research, Klinikum der Universität München, Ludwig Maximilian University of Munich, 81377 Munich, Germany.
authors.forename: Franziska
authors.initials: F
authors.lastname: Krammer
authors.affiliation: Institute for Stroke and Dementia Research, Klinikum der Universität München, Ludwig Maximilian University of Munich, 81377 Munich, Germany.
authors.forename: Gemma
authors.initials: G
authors.lastname: Llovera
authors.affiliation: Department of Neuroscience, Genentech, Inc., South San Francisco, California 94080.
authors.forename: Karpagam
authors.identifier: 0000-0001-8887-2767
authors.initials: K
authors.lastname: Srinivasan
authors.affiliation: Department of Neuroscience, Genentech, Inc., South San Francisco, California 94080.
authors.forename: David V
authors.identifier: 0000-0001-9679-7189
authors.initials: DV
authors.lastname: Hansen
authors.affiliation: Institute for Stroke and Dementia Research, Klinikum der Universität München, Ludwig Maximilian University of Munich, 81377 Munich, Germany, Munich Cluster for Systems Neurology (SyNergy), 81377 Munich, Germany, Graduate School of Neuroscience Munich, 82152 Planegg-Martinsried, Germany, and.
authors.forename: Arthur
authors.identifier: 0000-0002-9069-2594
authors.initials: A
authors.lastname: Liesz
authors.affiliation: Department of Neuroscience, Genentech, Inc., South San Francisco, California 94080.
authors.forename: Kimberly A
authors.identifier: 0000-0003-0568-802X
authors.initials: KA
authors.lastname: Scearce-Levie
authors.affiliation: Department of Neuroscience, Genentech, Inc., South San Francisco, California 94080.
authors.forename: Morgan
authors.identifier: 0000-0002-8703-5366
authors.initials: M
authors.lastname: Sheng
mesh_terms: D000818:Animals; D001921:Brain / Q000473:pathology; D000070642:Brain Injuries, Traumatic / Q000150:complications*; D000073883:CX3C Chemokine Receptor 1; D002135:Calcium-Binding Proteins / Q000378:metabolism; D002908:Chronic Disease; D049229:Dendritic Spines / Q000276:immunology / Q000473:pathology / Q000648:ultrastructure; D004195:Disease Models, Animal; D005106:Exploratory Behavior / Q000502:physiology; D005260:Female; D007249:Inflammation / Q000209:etiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008840:Microfilament Proteins / Q000378:metabolism; D009043:Motor Activity; D009410:Nerve Degeneration / Q000000981:diagnostic imaging / Q000209:etiology / Q000473:pathology; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D011597:Psychomotor Performance / Q000502:physiology; D019707:Receptors, Chemokine / Q000235:genetics / Q000378:metabolism; D020127:Recovery of Function / Q000502:physiology*; D013997:Time Factors
chemical_list: C491049:Aif1 protein, mouse; D000073883:CX3C Chemokine Receptor 1; D002135:Calcium-Binding Proteins; C471885:Cx3cr1 protein, mouse; D008840:Microfilament Proteins; D019707:Receptors, Chemokine
keywords: 3D imaging; axon; degeneration; inflammation; spine; trauma