title: Rapid neuroinflammatory response localized to injured neurons after diffuse traumatic brain injury in swine.
abstract: Despite increasing appreciation of the critical role that neuroinflammatory pathways play in brain injury and neurodegeneration, little is known about acute microglial reactivity following diffuse traumatic brain injury (TBI) - the most common clinical presentation that includes all concussions. Therefore, we investigated acute microglial reactivity using a porcine model of closed-head rotational velocity/acceleration-induced TBI that closely mimics the biomechanical etiology of inertial TBI in humans. We observed rapid microglial reactivity within 15min of both mild and severe TBI. Strikingly, microglial activation was restrained to regions proximal to individual injured neurons - as denoted by trauma-induced plasma membrane disruption - which served as epicenters of acute reactivity. Single-cell quantitative analysis showed that in areas free of traumatically permeabilized neurons, microglial density and morphology were similar between sham or following mild or severe TBI. However, microglia density increased and morphology shifted to become more reactive in proximity to injured neurons. Microglial reactivity around injured neurons was exacerbated following repetitive TBI, suggesting further amplification of acute neuroinflammatory responses. These results indicate that neuronal trauma rapidly activates microglia in a highly localized manner, and suggest that activated microglia may rapidly influence neuronal stability and/or pathophysiology after diffuse TBI.
authors.affiliation: Center for Neurotrauma, Neurodegeneration & Restoration, Corporal Michael J. Crescenz Veterans Affairs Medical Center, 3900 Woodland Avenue, Philadelphia, PA 19104, USA; School of Biomedical Engineering, Science and Health Systems, Drexel University, 3141 Chestnut Street, Philadelphia, PA 19104, USA; Center for Brain Injury & Repair, Department of Neurosurgery, University of Pennsylvania, 105 Hayden Hall, 3320 Smith Walk, Philadelphia, PA 19104, USA. Electronic address: kate.wofford@drexel.edu.
authors.forename: Kathryn L
authors.initials: KL
authors.lastname: Wofford
authors.affiliation: Center for Neurotrauma, Neurodegeneration & Restoration, Corporal Michael J. Crescenz Veterans Affairs Medical Center, 3900 Woodland Avenue, Philadelphia, PA 19104, USA; Center for Brain Injury & Repair, Department of Neurosurgery, University of Pennsylvania, 105 Hayden Hall, 3320 Smith Walk, Philadelphia, PA 19104, USA. Electronic address: jph18@case.edu.
authors.forename: James P
authors.initials: JP
authors.lastname: Harris
authors.affiliation: Center for Neurotrauma, Neurodegeneration & Restoration, Corporal Michael J. Crescenz Veterans Affairs Medical Center, 3900 Woodland Avenue, Philadelphia, PA 19104, USA; Center for Brain Injury & Repair, Department of Neurosurgery, University of Pennsylvania, 105 Hayden Hall, 3320 Smith Walk, Philadelphia, PA 19104, USA. Electronic address: kbrowne@mail.med.upenn.edu.
authors.forename: Kevin D
authors.initials: KD
authors.lastname: Browne
authors.affiliation: Center for Neurotrauma, Neurodegeneration & Restoration, Corporal Michael J. Crescenz Veterans Affairs Medical Center, 3900 Woodland Avenue, Philadelphia, PA 19104, USA; Center for Brain Injury & Repair, Department of Neurosurgery, University of Pennsylvania, 105 Hayden Hall, 3320 Smith Walk, Philadelphia, PA 19104, USA. Electronic address: dbrow@mail.med.upenn.edu.
authors.forename: Daniel P
authors.initials: DP
authors.lastname: Brown
authors.affiliation: Center for Neurotrauma, Neurodegeneration & Restoration, Corporal Michael J. Crescenz Veterans Affairs Medical Center, 3900 Woodland Avenue, Philadelphia, PA 19104, USA; Center for Brain Injury & Repair, Department of Neurosurgery, University of Pennsylvania, 105 Hayden Hall, 3320 Smith Walk, Philadelphia, PA 19104, USA. Electronic address: mgrovola@mail.med.upenn.edu.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Grovola
authors.affiliation: Center for Brain Injury & Repair, Department of Neurosurgery, University of Pennsylvania, 105 Hayden Hall, 3320 Smith Walk, Philadelphia, PA 19104, USA. Electronic address: mietusc@gmail.com.
authors.forename: Constance J
authors.initials: CJ
authors.lastname: Mietus
authors.affiliation: Center for Neurotrauma, Neurodegeneration & Restoration, Corporal Michael J. Crescenz Veterans Affairs Medical Center, 3900 Woodland Avenue, Philadelphia, PA 19104, USA; Center for Brain Injury & Repair, Department of Neurosurgery, University of Pennsylvania, 105 Hayden Hall, 3320 Smith Walk, Philadelphia, PA 19104, USA. Electronic address: wolfjo@upenn.edu.
authors.forename: John A
authors.initials: JA
authors.lastname: Wolf
authors.affiliation: Center for Neurotrauma, Neurodegeneration & Restoration, Corporal Michael J. Crescenz Veterans Affairs Medical Center, 3900 Woodland Avenue, Philadelphia, PA 19104, USA; Department of Neurology, University of Pennsylvania, 300 Dulles Building, 3400 Spruce Street, Philadelphia, PA 19104, USA. Electronic address: john.duda@va.gov.
authors.forename: John E
authors.initials: JE
authors.lastname: Duda
authors.affiliation: Department of Biostatistics and Epidemiology, Hospital of the University of Pennsylvania, 621 Blockley Hall, 423 Guardian Drive, Philadelphia, PA 19104, USA. Electronic address: mputt@mail.med.upenn.edu.
authors.forename: Mary E
authors.initials: ME
authors.lastname: Putt
authors.affiliation: School of Biomedical Engineering, Science and Health Systems, Drexel University, 3141 Chestnut Street, Philadelphia, PA 19104, USA. Electronic address: kls35@drexel.edu.
authors.forename: Kara L
authors.initials: KL
authors.lastname: Spiller
authors.affiliation: Center for Neurotrauma, Neurodegeneration & Restoration, Corporal Michael J. Crescenz Veterans Affairs Medical Center, 3900 Woodland Avenue, Philadelphia, PA 19104, USA; Center for Brain Injury & Repair, Department of Neurosurgery, University of Pennsylvania, 105 Hayden Hall, 3320 Smith Walk, Philadelphia, PA 19104, USA. Electronic address: dkacy@mail.med.upenn.edu.
authors.forename: D Kacy
authors.initials: DK
authors.lastname: Cullen
mesh_terms: D000818:Animals; D000070642:Brain Injuries, Traumatic / Q000473:pathology*; D002462:Cell Membrane / Q000473:pathology; D020833:Diffuse Axonal Injury / Q000473:pathology; D005260:Female; D016489:Head Injuries, Closed / Q000473:pathology; D007150:Immunohistochemistry; D007249:Inflammation / Q000473:pathology*; D017628:Microglia / Q000473:pathology; D009474:Neurons / Q000473:pathology*; D013552:Swine
keywords: Concussion; Diffuse traumatic brain injury; Microglia reactivity; Neuroinflammation; Permeabilized neurons