Treatment with an interleukin-1 receptor antagonist mitigates neuroinflammation and brain damage after polytrauma

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Abstract

Traumatic brain injury (TBI) and long bone fracture are common in polytrauma. This injury combination in mice results in elevated levels of the pro-inflammatory cytokine interleukin-1β (IL-1β) and exacerbated neuropathology when compared to isolated-TBI. Here we examined the effect of treatment with an IL-1 receptor antagonist (IL-1ra) in mice given a TBI and a concomitant tibial fracture (i.e., polytrauma). Adult male C57BL/6 mice were given sham-injuries or polytrauma and treated with saline-vehicle or IL-1ra (100. mg/kg). Treatments were subcutaneously injected at 1, 6, and 24. h, and then once daily for one week post-injury. 7-8 mice/group were euthanized at 48. h post-injury. 12-16 mice/group underwent behavioral testing at 12. weeks post-injury and MRI at 14. weeks post-injury before being euthanized at 16. weeks post-injury. At 48. h post-injury, markers for activated microglia and astrocytes, as well as neutrophils and edema, were decreased in polytrauma mice treated with IL-1ra compared to polytrauma mice treated with vehicle. At 14. weeks post-injury, MRI analysis demonstrated that IL-1ra treatment after polytrauma reduced volumetric loss in the injured cortex and mitigated track-weighted MRI markers for axonal injury. As IL-1ra (Anakinra) is approved for human use, it may represent a promising therapy in polytrauma cases involving TBI and fracture.

Original languageEnglish
Pages (from-to)359-371
Number of pages13
JournalBrain, Behavior, and Immunity
Volume66
DOIs
Publication statusPublished - Nov 2017

Keywords

  • Fracture
  • IL-1β
  • MRI
  • Multitrauma
  • Neuroinflammation
  • Traumatic brain injury

Cite this

@article{ce94d8f8674c42839ff9b71335e8d122,
title = "Treatment with an interleukin-1 receptor antagonist mitigates neuroinflammation and brain damage after polytrauma",
abstract = "Traumatic brain injury (TBI) and long bone fracture are common in polytrauma. This injury combination in mice results in elevated levels of the pro-inflammatory cytokine interleukin-1β (IL-1β) and exacerbated neuropathology when compared to isolated-TBI. Here we examined the effect of treatment with an IL-1 receptor antagonist (IL-1ra) in mice given a TBI and a concomitant tibial fracture (i.e., polytrauma). Adult male C57BL/6 mice were given sham-injuries or polytrauma and treated with saline-vehicle or IL-1ra (100. mg/kg). Treatments were subcutaneously injected at 1, 6, and 24. h, and then once daily for one week post-injury. 7-8 mice/group were euthanized at 48. h post-injury. 12-16 mice/group underwent behavioral testing at 12. weeks post-injury and MRI at 14. weeks post-injury before being euthanized at 16. weeks post-injury. At 48. h post-injury, markers for activated microglia and astrocytes, as well as neutrophils and edema, were decreased in polytrauma mice treated with IL-1ra compared to polytrauma mice treated with vehicle. At 14. weeks post-injury, MRI analysis demonstrated that IL-1ra treatment after polytrauma reduced volumetric loss in the injured cortex and mitigated track-weighted MRI markers for axonal injury. As IL-1ra (Anakinra) is approved for human use, it may represent a promising therapy in polytrauma cases involving TBI and fracture.",
keywords = "Fracture, IL-1β, MRI, Multitrauma, Neuroinflammation, Traumatic brain injury",
author = "Mujun Sun and Brady, {Rhys D.} and Wright, {David K.} and Kim, {Hyun Ah} and Zhang, {Shenpeng R.} and Sobey, {Christopher G.} and Johnstone, {Maddison R.} and O'Brien, {Terence J.} and Semple, {Bridgette D.} and McDonald, {Stuart J.} and Shultz, {Sandy R.}",
year = "2017",
month = "11",
doi = "10.1016/j.bbi.2017.08.005",
language = "English",
volume = "66",
pages = "359--371",
journal = "Brain, Behavior, and Immunity",
issn = "0889-1591",
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TY - JOUR

T1 - Treatment with an interleukin-1 receptor antagonist mitigates neuroinflammation and brain damage after polytrauma

AU - Sun, Mujun

AU - Brady, Rhys D.

AU - Wright, David K.

AU - Kim, Hyun Ah

AU - Zhang, Shenpeng R.

AU - Sobey, Christopher G.

AU - Johnstone, Maddison R.

AU - O'Brien, Terence J.

AU - Semple, Bridgette D.

AU - McDonald, Stuart J.

AU - Shultz, Sandy R.

PY - 2017/11

Y1 - 2017/11

N2 - Traumatic brain injury (TBI) and long bone fracture are common in polytrauma. This injury combination in mice results in elevated levels of the pro-inflammatory cytokine interleukin-1β (IL-1β) and exacerbated neuropathology when compared to isolated-TBI. Here we examined the effect of treatment with an IL-1 receptor antagonist (IL-1ra) in mice given a TBI and a concomitant tibial fracture (i.e., polytrauma). Adult male C57BL/6 mice were given sham-injuries or polytrauma and treated with saline-vehicle or IL-1ra (100. mg/kg). Treatments were subcutaneously injected at 1, 6, and 24. h, and then once daily for one week post-injury. 7-8 mice/group were euthanized at 48. h post-injury. 12-16 mice/group underwent behavioral testing at 12. weeks post-injury and MRI at 14. weeks post-injury before being euthanized at 16. weeks post-injury. At 48. h post-injury, markers for activated microglia and astrocytes, as well as neutrophils and edema, were decreased in polytrauma mice treated with IL-1ra compared to polytrauma mice treated with vehicle. At 14. weeks post-injury, MRI analysis demonstrated that IL-1ra treatment after polytrauma reduced volumetric loss in the injured cortex and mitigated track-weighted MRI markers for axonal injury. As IL-1ra (Anakinra) is approved for human use, it may represent a promising therapy in polytrauma cases involving TBI and fracture.

AB - Traumatic brain injury (TBI) and long bone fracture are common in polytrauma. This injury combination in mice results in elevated levels of the pro-inflammatory cytokine interleukin-1β (IL-1β) and exacerbated neuropathology when compared to isolated-TBI. Here we examined the effect of treatment with an IL-1 receptor antagonist (IL-1ra) in mice given a TBI and a concomitant tibial fracture (i.e., polytrauma). Adult male C57BL/6 mice were given sham-injuries or polytrauma and treated with saline-vehicle or IL-1ra (100. mg/kg). Treatments were subcutaneously injected at 1, 6, and 24. h, and then once daily for one week post-injury. 7-8 mice/group were euthanized at 48. h post-injury. 12-16 mice/group underwent behavioral testing at 12. weeks post-injury and MRI at 14. weeks post-injury before being euthanized at 16. weeks post-injury. At 48. h post-injury, markers for activated microglia and astrocytes, as well as neutrophils and edema, were decreased in polytrauma mice treated with IL-1ra compared to polytrauma mice treated with vehicle. At 14. weeks post-injury, MRI analysis demonstrated that IL-1ra treatment after polytrauma reduced volumetric loss in the injured cortex and mitigated track-weighted MRI markers for axonal injury. As IL-1ra (Anakinra) is approved for human use, it may represent a promising therapy in polytrauma cases involving TBI and fracture.

KW - Fracture

KW - IL-1β

KW - MRI

KW - Multitrauma

KW - Neuroinflammation

KW - Traumatic brain injury

UR - http://www.scopus.com/inward/record.url?scp=85028307091&partnerID=8YFLogxK

U2 - 10.1016/j.bbi.2017.08.005

DO - 10.1016/j.bbi.2017.08.005

M3 - Article

VL - 66

SP - 359

EP - 371

JO - Brain, Behavior, and Immunity

JF - Brain, Behavior, and Immunity

SN - 0889-1591

ER -