Fractalkine receptor deficiency is associated with early protection but late worsening of outcome following brain trauma in mice

Elisa R. Zanier, Federica Marchesi, Fabrizio Ortolano, Carlo Perego, Maedeh Arabian, Tommaso Zoerle, Eliana Sammali, Francesca Pischiutta, Maria Grazia De Simoni

Research output: Contribution to journalArticle

27 Citations (Scopus)

Abstract

An impaired ability to regulate microglia activation by fractalkine (CX3CL1) leads to microglia chronic sub-activation. How this condition affects outcome after acute brain injury is still debated, with studies showing contrasting results depending on the timing and the brain pathology. Here, we investigated the early and delayed consequences of fractalkine receptor (CX3CR1) deletion on neurological outcome and on the phenotypical features of the myeloid cells present in the lesions of mice with traumatic brain injury (TBI). Wild type (WT) and CX3CR1-/- C57Bl/6 mice were subjected to sham or controlled cortical impact brain injury. Outcome was assessed at 4 days and 5 weeks after TBI by neuroscore, neuronal count, and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining. Compared with WT mice, CX3CR1-/- TBI mice showed a significant reduction of sensorimotor deficits and lower cellular damage in the injured cortex 4 days post-TBI. Conversely, at 5 weeks, they showed a worsening of sensorimotor deficits and pericontusional cell death. Microglia (M) and macrophage (μ) activation and polarization were assessed by quantitative immunohistochemistry for CD11b, CD68, Ym1, and inducible nitric oxide synthase (iNOS) - markers of M/μ activation, phagocytosis, M2, and M1 phenotypes, respectively. Morphological analysis revealed a decreased area and perimeter of CD11b+ cells in CX3CR1-/- mice at 4 days post-TBI, whereas, at 5 weeks, both parameters were significantly higher, compared with WT mice. At 4 days, CX3CR1-/- mice showed significantly decreased CD68 and iNOS immunoreactivity, while at 5 weeks post-injury, they showed a selective increase of iNOS. Gene expression on CD11b+ sorted cells revealed an increase of interleukin 10 and insulin-like growth factor 1 (IGF1) at 1 day and a decrease of IGF1 4 days and 5 weeks post-TBI in CX3CR1-/-, compared with WT mice. These data show an early protection followed by a chronic exacerbation of TBI outcome in the absence of CX3CR1. Thus, longitudinal effects of myeloid cell manipulation at different stages of pathology should be investigated to understand how and when their modulation may offer therapeutic chances.

Original languageEnglish
Pages (from-to)1060-1072
Number of pages13
JournalJournal of Neurotrauma
Volume33
Issue number11
DOIs
Publication statusPublished - Jun 1 2016

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Microglia
Nitric Oxide Synthase Type II
Somatomedins
Myeloid Cells
Brain Injuries
Chemokine CX3CL1
Pathology
DNA Nucleotidylexotransferase
Macrophage Activation
Traumatic Brain Injury
V28 receptor
Phagocytosis
Interleukin-10
Cell Death
Immunohistochemistry
Staining and Labeling
Phenotype
Gene Expression
Wounds and Injuries
Brain

Keywords

  • fractalkine receptor
  • inflammation
  • macrophages
  • microglia
  • traumatic brain injury

ASJC Scopus subject areas

  • Clinical Neurology

Cite this

Fractalkine receptor deficiency is associated with early protection but late worsening of outcome following brain trauma in mice. / Zanier, Elisa R.; Marchesi, Federica; Ortolano, Fabrizio; Perego, Carlo; Arabian, Maedeh; Zoerle, Tommaso; Sammali, Eliana; Pischiutta, Francesca; De Simoni, Maria Grazia.

In: Journal of Neurotrauma, Vol. 33, No. 11, 01.06.2016, p. 1060-1072.

Research output: Contribution to journalArticle

Zanier, Elisa R. ; Marchesi, Federica ; Ortolano, Fabrizio ; Perego, Carlo ; Arabian, Maedeh ; Zoerle, Tommaso ; Sammali, Eliana ; Pischiutta, Francesca ; De Simoni, Maria Grazia. / Fractalkine receptor deficiency is associated with early protection but late worsening of outcome following brain trauma in mice. In: Journal of Neurotrauma. 2016 ; Vol. 33, No. 11. pp. 1060-1072.
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