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Updated: Apr 4, 2026
Electromagnetic Controlled Closed-Head Model of Mild Traumatic Brain Injury in Mice
Published on: September 28, 2022
Time-dependent effects of CX3CR1 in a mouse model of mild traumatic brain injury
Heidi Y Febinger1,2, Hannah E Thomasy1,3, Maria N Pavlova1
1Department of Anesthesiology and Pain Medicine, University of Washington, BOX # 359724, Seattle, WA, 98001, USA.
Background:
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). 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.
Methods:
In 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.
Results:
During 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.
Conclusion:
Collectively, 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.
Insights
Fractalkine signaling (CX3CL1/CX3CR1) has a dual role in traumatic brain injury (TBI). Deleting CX3CR1 initially protects against TBI but leads to worse outcomes later, highlighting time-dependent effects on microglia.
Area of Science:
- Neuroscience
- Immunology
- Cell Biology
Background:
- Neuroinflammation is a key factor in long-term outcomes after traumatic brain injury (TBI).
- Microglia, the brain's immune cells, have complex roles in injury and recovery.
- Fractalkine (CX3CL1) and its receptor CX3CR1 mediate neuron-microglia interactions, influencing microglia activation and disease outcomes.
Purpose of the Study:
- To investigate the role of CX3CR1 signaling in the acute and chronic phases following mild TBI.
- To evaluate the impact of CX3CR1 deficiency on histopathology, cell death, microglia activation, and cognitive function post-TBI.
Main Methods:
- Utilized a controlled cortical impact (CCI) model of mild TBI in mice genetically deficient in CX3CR1.
- Assessed outcomes including motor deficits, neuronal cell death, microglia phenotypes (M1/M2 markers), and cognitive function up to 30 days post-injury.
Main Results:
- In the acute phase (24h-15d), CX3CR1(-/-) mice showed reduced motor deficits and cell death compared to wild-type.
- In the chronic phase (30d), CX3CR1(-/-) mice exhibited worse cognitive dysfunction and increased neuronal death.
- CX3CR1 deficiency shifted microglia towards an anti-inflammatory M2 phenotype acutely and a pro-inflammatory M1 phenotype chronically.
Conclusions:
- CX3CL1/CX3CR1 signaling plays a time-dependent role in the response to mild TBI.
- Distinct microglia phenotypes appear to mediate the acute protective and chronic detrimental effects observed in CX3CR1-deficient mice after TBI.
