Tumor necrosis factor in traumatic brain injury

Effects of genetic deletion of p55 or p75 receptor

Luca Longhi, Carlo Perego, Fabrizio Ortolano, Silvia Aresi, Stefano Fumagalli, Elisa R. Zanier, Nino Stocchetti, Maria Grazia De Simoni

Research output: Contribution to journalArticle

30 Citations (Scopus)

Abstract

The role of tumor necrosis factor (TNF) and its receptors after traumatic brain injury (TBI) remains unclear. We evaluated the effects of genetic deletion of either p55 or p75 TNF receptor on neurobehavioral outcome, histopathology, DNA damage and apoptosis-related cell death/survival gene expression (bcl-2/bax), and microglia/macrophage (M/M) activation in wild-type (WT) and knockout mice after TBI. Injured p55 (-/-) mice showed a significant attenuation while p75 (-/-) mice showed a significant worsening of sensorimotor deficits compared with WT mice over 4 weeks postinjury. At the same time point, contusion volume in p55 (-/-) mice (11.1±3.3 mm 3) was significantly reduced compared with WT (19.7±3.4 mm 3) and p75 (-/-) mice (20.9±3.2 mm 3). At 4 hours postinjury, bcl-2/bax ratio mRNA expression was increased in p55 (-/-) compared with p75 (-/-) mice and was associated with reduced DNA damage terminal deoxynucleotidyl transferaseYmediated dUTP nick end labeling (TUNEL-positivity), reduced CD11b expression and increased Ym1 expression at 24 hours postinjury in p55 (-/-) compared with p75 (-/-) mice, indicative of a protective M/M response. These data suggest that TNF may exacerbate neurobehavioral deficits and tissue damage via p55 TNF receptor whose inhibition may represent a specific therapeutic target after TBI.

Original languageEnglish
Pages (from-to)1182-1189
Number of pages8
JournalJournal of Cerebral Blood Flow and Metabolism
Volume33
Issue number8
DOIs
Publication statusPublished - Aug 2013

Fingerprint

Tumor Necrosis Factor-alpha
Tumor Necrosis Factor Receptors
Microglia
DNA Damage
Macrophage Activation
Contusions
In Situ Nick-End Labeling
Traumatic Brain Injury
Knockout Mice
Cell Survival
Cell Death
Macrophages
Apoptosis
Gene Expression
Messenger RNA

Keywords

  • apoptosis
  • inflammation
  • microglia
  • pathophysiology
  • traumatic brain injury
  • tumor necrosis factor

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Clinical Neurology
  • Neurology

Cite this

Tumor necrosis factor in traumatic brain injury : Effects of genetic deletion of p55 or p75 receptor. / Longhi, Luca; Perego, Carlo; Ortolano, Fabrizio; Aresi, Silvia; Fumagalli, Stefano; Zanier, Elisa R.; Stocchetti, Nino; De Simoni, Maria Grazia.

In: Journal of Cerebral Blood Flow and Metabolism, Vol. 33, No. 8, 08.2013, p. 1182-1189.

Research output: Contribution to journalArticle

@article{d8a7bf506350414b8e3b6b5376893fa7,
title = "Tumor necrosis factor in traumatic brain injury: Effects of genetic deletion of p55 or p75 receptor",
abstract = "The role of tumor necrosis factor (TNF) and its receptors after traumatic brain injury (TBI) remains unclear. We evaluated the effects of genetic deletion of either p55 or p75 TNF receptor on neurobehavioral outcome, histopathology, DNA damage and apoptosis-related cell death/survival gene expression (bcl-2/bax), and microglia/macrophage (M/M) activation in wild-type (WT) and knockout mice after TBI. Injured p55 (-/-) mice showed a significant attenuation while p75 (-/-) mice showed a significant worsening of sensorimotor deficits compared with WT mice over 4 weeks postinjury. At the same time point, contusion volume in p55 (-/-) mice (11.1±3.3 mm 3) was significantly reduced compared with WT (19.7±3.4 mm 3) and p75 (-/-) mice (20.9±3.2 mm 3). At 4 hours postinjury, bcl-2/bax ratio mRNA expression was increased in p55 (-/-) compared with p75 (-/-) mice and was associated with reduced DNA damage terminal deoxynucleotidyl transferaseYmediated dUTP nick end labeling (TUNEL-positivity), reduced CD11b expression and increased Ym1 expression at 24 hours postinjury in p55 (-/-) compared with p75 (-/-) mice, indicative of a protective M/M response. These data suggest that TNF may exacerbate neurobehavioral deficits and tissue damage via p55 TNF receptor whose inhibition may represent a specific therapeutic target after TBI.",
keywords = "apoptosis, inflammation, microglia, pathophysiology, traumatic brain injury, tumor necrosis factor",
author = "Luca Longhi and Carlo Perego and Fabrizio Ortolano and Silvia Aresi and Stefano Fumagalli and Zanier, {Elisa R.} and Nino Stocchetti and {De Simoni}, {Maria Grazia}",
year = "2013",
month = "8",
doi = "10.1038/jcbfm.2013.65",
language = "English",
volume = "33",
pages = "1182--1189",
journal = "Journal of Cerebral Blood Flow and Metabolism",
issn = "0271-678X",
publisher = "Nature Publishing Group",
number = "8",

}

TY - JOUR

T1 - Tumor necrosis factor in traumatic brain injury

T2 - Effects of genetic deletion of p55 or p75 receptor

AU - Longhi, Luca

AU - Perego, Carlo

AU - Ortolano, Fabrizio

AU - Aresi, Silvia

AU - Fumagalli, Stefano

AU - Zanier, Elisa R.

AU - Stocchetti, Nino

AU - De Simoni, Maria Grazia

PY - 2013/8

Y1 - 2013/8

N2 - The role of tumor necrosis factor (TNF) and its receptors after traumatic brain injury (TBI) remains unclear. We evaluated the effects of genetic deletion of either p55 or p75 TNF receptor on neurobehavioral outcome, histopathology, DNA damage and apoptosis-related cell death/survival gene expression (bcl-2/bax), and microglia/macrophage (M/M) activation in wild-type (WT) and knockout mice after TBI. Injured p55 (-/-) mice showed a significant attenuation while p75 (-/-) mice showed a significant worsening of sensorimotor deficits compared with WT mice over 4 weeks postinjury. At the same time point, contusion volume in p55 (-/-) mice (11.1±3.3 mm 3) was significantly reduced compared with WT (19.7±3.4 mm 3) and p75 (-/-) mice (20.9±3.2 mm 3). At 4 hours postinjury, bcl-2/bax ratio mRNA expression was increased in p55 (-/-) compared with p75 (-/-) mice and was associated with reduced DNA damage terminal deoxynucleotidyl transferaseYmediated dUTP nick end labeling (TUNEL-positivity), reduced CD11b expression and increased Ym1 expression at 24 hours postinjury in p55 (-/-) compared with p75 (-/-) mice, indicative of a protective M/M response. These data suggest that TNF may exacerbate neurobehavioral deficits and tissue damage via p55 TNF receptor whose inhibition may represent a specific therapeutic target after TBI.

AB - The role of tumor necrosis factor (TNF) and its receptors after traumatic brain injury (TBI) remains unclear. We evaluated the effects of genetic deletion of either p55 or p75 TNF receptor on neurobehavioral outcome, histopathology, DNA damage and apoptosis-related cell death/survival gene expression (bcl-2/bax), and microglia/macrophage (M/M) activation in wild-type (WT) and knockout mice after TBI. Injured p55 (-/-) mice showed a significant attenuation while p75 (-/-) mice showed a significant worsening of sensorimotor deficits compared with WT mice over 4 weeks postinjury. At the same time point, contusion volume in p55 (-/-) mice (11.1±3.3 mm 3) was significantly reduced compared with WT (19.7±3.4 mm 3) and p75 (-/-) mice (20.9±3.2 mm 3). At 4 hours postinjury, bcl-2/bax ratio mRNA expression was increased in p55 (-/-) compared with p75 (-/-) mice and was associated with reduced DNA damage terminal deoxynucleotidyl transferaseYmediated dUTP nick end labeling (TUNEL-positivity), reduced CD11b expression and increased Ym1 expression at 24 hours postinjury in p55 (-/-) compared with p75 (-/-) mice, indicative of a protective M/M response. These data suggest that TNF may exacerbate neurobehavioral deficits and tissue damage via p55 TNF receptor whose inhibition may represent a specific therapeutic target after TBI.

KW - apoptosis

KW - inflammation

KW - microglia

KW - pathophysiology

KW - traumatic brain injury

KW - tumor necrosis factor

UR - http://www.scopus.com/inward/record.url?scp=84881190695&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84881190695&partnerID=8YFLogxK

U2 - 10.1038/jcbfm.2013.65

DO - 10.1038/jcbfm.2013.65

M3 - Article

VL - 33

SP - 1182

EP - 1189

JO - Journal of Cerebral Blood Flow and Metabolism

JF - Journal of Cerebral Blood Flow and Metabolism

SN - 0271-678X

IS - 8

ER -