title: Fractalkine Receptor Deficiency Is Associated with Early Protection but Late Worsening of Outcome following Brain Trauma in Mice.
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.
authors.affiliation: 1 Department of Neuroscience, IRCCS-Istituto di Recerche Farmacologiche Mario Negri , Milan, Italy .
authors.forename: Elisa R
authors.initials: ER
authors.lastname: Zanier
authors.affiliation: 1 Department of Neuroscience, IRCCS-Istituto di Recerche Farmacologiche Mario Negri , Milan, Italy .
authors.forename: Federica
authors.initials: F
authors.lastname: Marchesi
authors.affiliation: 2 Neuroscience ICU, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico , Milan, Italy .
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Ortolano
authors.affiliation: 1 Department of Neuroscience, IRCCS-Istituto di Recerche Farmacologiche Mario Negri , Milan, Italy .
authors.forename: Carlo
authors.initials: C
authors.lastname: Perego
authors.affiliation: 1 Department of Neuroscience, IRCCS-Istituto di Recerche Farmacologiche Mario Negri , Milan, Italy .|3 Department of Physiology, Faculty of Medicine, Tehran University of Medical Science , Tehran, Iran .
authors.forename: Maedeh
authors.initials: M
authors.lastname: Arabian
authors.affiliation: 2 Neuroscience ICU, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico , Milan, Italy .
authors.forename: Tommaso
authors.initials: T
authors.lastname: Zoerle
authors.affiliation: 1 Department of Neuroscience, IRCCS-Istituto di Recerche Farmacologiche Mario Negri , Milan, Italy .|4 Fondazione IRCCS Istituto Neurologico Carlo Besta , Milan, Italy .
authors.forename: Eliana
authors.initials: E
authors.lastname: Sammali
authors.affiliation: 1 Department of Neuroscience, IRCCS-Istituto di Recerche Farmacologiche Mario Negri , Milan, Italy .
authors.forename: Francesca
authors.initials: F
authors.lastname: Pischiutta
authors.affiliation: 1 Department of Neuroscience, IRCCS-Istituto di Recerche Farmacologiche Mario Negri , Milan, Italy .
authors.forename: Maria-Grazia
authors.initials: MG
authors.lastname: De Simoni
mesh_terms: D000818:Animals; D000070642:Brain Injuries, Traumatic / Q000378:metabolism* / Q000473:pathology* / Q000503:physiopathology*; D000073883:CX3C Chemokine Receptor 1 / Q000172:deficiency / Q000502:physiology*; D004195:Disease Models, Animal; D018450:Disease Progression; D008262:Macrophage Activation; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017628:Microglia / Q000378:metabolism*; D065840:Protective Factors; D013997:Time Factors
chemical_list: D000073883:CX3C Chemokine Receptor 1; C471885:Cx3cr1 protein, mouse
keywords: fractalkine receptor; inflammation; macrophages; microglia; traumatic brain injury