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 (l) activation and polarization were assessed by quantitative immunohistochemistry for CD11b, CD68, Ym1, and inducible nitric oxide synthase (iNOS)-markers of M/l 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.

Pinocembrin protects hemorrhagic brain primarily by inhibiting toll-like receptor 4 and reducing M1 phenotype microglia

“…In recent years, it was reported that an M2-to-M1 microglia/macrophage switch occurs in spinal cord injury (Kigerl et al, 2009) and ischemic stroke (Hu et al, 2012), whereas a mixed M1 and M2 population is seen in traumatic brain injury (Morganti et al, 2016; Zanier et al, 2016). The microglial M1-to-M2 phenotype transition we observed in the ICH brain may result from phenotypic transformation of microglia in the early stage of ICH or result from M2-like microglial migration or M2-like macrophage infiltration.…”

Modulators of microglial activation and polarization after intracerebral haemorrhage

“…Nevertheless, M2 microglia do have important functions in phagocytosis and toxicity clearance in other brain diseases 77 , such as ischaemic stroke 17,78 , TBI 79 and epilepsy 31 , suggesting that the function of M2 microglia in ICH should be explored.…”

Emerging Roles for the Immune System in Traumatic Brain Injury

“…A recent study by Zanier et al used CX3CR1 knockout mice to disrupt CX3CL1 chemokine signaling in order to understand its importance in controlling myeloid cell activity in TBI (50). After receiving a CCI injury, CX3CR1 knockout animals showed neurological protection 4 days following TBI.…”