Abstract
BackgroundNeuroinflammation is an important secondary mechanism that is a key mediator of the long-term consequences of neuronal injury that occur in traumatic brain injury (TBI). Microglia are highly plastic cells with dual roles in neuronal injury and recovery. Recent studies suggest that the chemokine fractalkine (CX3CL1, FKN) mediates neural/microglial interactions via its sole receptor CX3CR1. CX3CL1/CX3CR1 signaling modulates microglia activation, and depending upon the type and time of injury, either protects or exacerbates neurological diseases.MethodsIn this study, mice deficient in CX3CR1 were subjected to mild controlled cortical impact injury (CCI), a model of TBI. We evaluated the effects of genetic deletion of CX3CR1 on histopathology, cell death/survival, microglia activation, and cognitive function for 30 days post-injury.ResultsDuring the acute post-injury period (24 h–15 days), motor deficits, cell death, and neuronal cell loss were more profound in injured wild-type than in CX3CR1−/− mice. In contrast, during the chronic period of 30 days post-TBI, injured CX3CR1−/− mice exhibited greater cognitive dysfunction and increased neuronal death than wild-type mice. The protective and deleterious effects of CX3CR1 were associated with changes in microglia phenotypes; during the acute phase CX3CR1−/− mice showed a predominant anti-inflammatory M2 microglial response, with increased expression of Ym1, CD206, and TGFβ. In contrast, increased M1 phenotypic microglia markers, Marco, and CD68 were predominant at 30 days post-TBI.ConclusionCollectively, these novel data demonstrate a time-dependent role for CX3CL1/CX3CR1 signaling after TBI and suggest that the acute and chronic responses to mild TBI are modulated in part by distinct microglia phenotypes.
Highlights
Neuroinflammation is an important secondary mechanism that is a key mediator of the long-term consequences of neuronal injury that occur in traumatic brain injury (TBI)
We demonstrate that lack of CX3CL1/ CX3CR1 signaling in the brain leads to delayed neuronal damage and neurologic and cognitive impairment after TBI that is associated with a switch in microglia phenotype
Mild TBI impairs neuromotor function Prior to surgery, there were no differences in composite neuroscores between WT and CX3CR1−/− mice
Summary
Neuroinflammation is an important secondary mechanism that is a key mediator of the long-term consequences of neuronal injury that occur in traumatic brain injury (TBI). CX3CR1 signaling in neurodegenerative disease is an intricate and highly debated research topic that is becoming even more complicated as new studies reveal seemingly discordant results. It appears that FKN/CX3CR1 signaling plays a direct role in neurodegeneration and/or neuroprotection depending upon the CNS insult. Both beneficial and detrimental effects of CX3CR1 deficiency are associated with microglia activation [9,10,11]. Other reports indicate that CX3CR1 deficiency attenuates amyloid deposition in AD mouse models characterized by extensive plaque deposition [18, 22]
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