Rapid neuroinflammatory response localized to injured neurons after diffuse traumatic brain injury in swine

Kathryn L Wofford; James P Harris; Kevin D Browne; Daniel P Brown; Michael R Grovola; Constance J Mietus; John A Wolf; John E Duda; Mary E Putt; Kara L Spiller; D Kacy Cullen

doi:10.1016/j.expneurol.2017.01.004

Rapid neuroinflammatory response localized to injured neurons after diffuse traumatic brain injury in swine

Exp Neurol. 2017 Apr:290:85-94. doi: 10.1016/j.expneurol.2017.01.004. Epub 2017 Jan 9.

Authors

Affiliations

¹ 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.
² 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.
³ 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.
⁴ 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.
⁵ 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.
⁶ 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.
⁷ 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.
⁸ 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.
⁹ 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.
¹⁰ School of Biomedical Engineering, Science and Health Systems, Drexel University, 3141 Chestnut Street, Philadelphia, PA 19104, USA. Electronic address: kls35@drexel.edu.
¹¹ 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.

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.

Keywords: Concussion; Diffuse traumatic brain injury; Microglia reactivity; Neuroinflammation; Permeabilized neurons.

Publication types

Research Support, N.I.H., Extramural
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Animals
Brain Injuries, Traumatic / pathology*
Cell Membrane / pathology
Diffuse Axonal Injury / pathology
Female
Head Injuries, Closed / pathology
Immunohistochemistry
Inflammation / pathology*
Microglia / pathology
Neurons / pathology*
Swine

Abstract

Publication types

MeSH terms

Grants and funding