title: Deletion of the Fractalkine Receptor, CX3CR1, Improves Endogenous Repair, Axon Sprouting, and Synaptogenesis after Spinal Cord Injury in Mice.
abstract: Impaired signaling via CX3CR1, the fractalkine receptor, promotes recovery after traumatic spinal contusion injury in mice, a benefit achieved in part by reducing macrophage-mediated injury at the lesion epicenter. Here, we tested the hypothesis that CX3CR1-dependent changes in microglia and macrophage functions also will enhance neuroplasticity, at and several segments below the injury epicenter. New data show that in the presence of inflammatory stimuli, CX3CR1-deficient (CX3CR1-/-) microglia and macrophages adopt a reparative phenotype and increase expression of genes that encode neurotrophic and gliogenic proteins. At the lesion epicenter (mid-thoracic spinal cord), the microenvironment created by CX3CR1-/-microglia/macrophages enhances NG2 cell responses, axon sparing, and sprouting of serotonergic axons. In lumbar spinal cord, inflammatory signaling is reduced in CX3CR1-/-microglia. This is associated with reduced dendritic pathology and improved axonal and synaptic plasticity on ventral horn motor neurons. Together, these data indicate that CX3CR1, a microglia-specific chemokine receptor, is a novel therapeutic target for enhancing neuroplasticity and recovery after SCI. Interventions that specifically target CX3CR1 could reduce the adverse effects of inflammation and augment activity-dependent plasticity and restoration of function. Indeed, limiting CX3CR1-dependent signaling could improve rehabilitation and spinal learning.SIGNIFICANCE STATEMENTPublished data show that genetic deletion of CX3CR1, a microglia-specific chemokine receptor, promotes recovery after traumatic spinal cord injury in mice, a benefit achieved in part by reducing macrophage-mediated injury at the lesion epicenter. Data in the current manuscript indicate that CX3CR1 deletion changes microglia and macrophage function, creating a tissue microenvironment that enhances endogenous repair and indices of neuroplasticity, at and several segments below the injury epicenter. Interventions that specifically target CX3CR1 might be used in the future to reduce the adverse effects of intraspinal inflammation and augment activity-dependent plasticity (e.g., rehabilitation) and restoration of function.
authors.affiliation: Department of Neuroscience and Center for Brain and Spinal Cord Repair, Ohio State University, Wexner Medical Center, Columbus, Ohio 43210.
authors.forename: Camila M
authors.identifier: 0000-0002-3171-8141
authors.initials: CM
authors.lastname: Freria
authors.affiliation: Department of Neuroscience and Center for Brain and Spinal Cord Repair, Ohio State University, Wexner Medical Center, Columbus, Ohio 43210.
authors.forename: Jodie C E
authors.identifier: 0000-0002-4820-6070
authors.initials: JC
authors.lastname: Hall
authors.affiliation: Department of Neuroscience and Center for Brain and Spinal Cord Repair, Ohio State University, Wexner Medical Center, Columbus, Ohio 43210.
authors.forename: Ping
authors.initials: P
authors.lastname: Wei
authors.affiliation: Department of Neuroscience and Center for Brain and Spinal Cord Repair, Ohio State University, Wexner Medical Center, Columbus, Ohio 43210.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Guan
authors.affiliation: Department of Neuroscience and Center for Brain and Spinal Cord Repair, Ohio State University, Wexner Medical Center, Columbus, Ohio 43210.
authors.forename: Dana M
authors.identifier: 0000-0001-7066-9701
authors.initials: DM
authors.lastname: McTigue
authors.affiliation: Department of Neuroscience and Center for Brain and Spinal Cord Repair, Ohio State University, Wexner Medical Center, Columbus, Ohio 43210 phillip.popovich@osumc.edu.
authors.forename: Phillip G
authors.identifier: 0000-0003-1329-7395
authors.initials: PG
authors.lastname: Popovich
mesh_terms: D000818:Animals; D000073883:CX3C Chemokine Receptor 1; D005260:Female; D017353:Gene Deletion; D015316:Genetic Therapy / Q000379:methods; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D000071446:Neuronal Outgrowth / Q000502:physiology*; D019707:Receptors, Chemokine / Q000235:genetics / Q000378:metabolism*; D013119:Spinal Cord Injuries / Q000473:pathology* / Q000503:physiopathology* / Q000628:therapy; D058630:Spinal Cord Regeneration / Q000502:physiology*; D013569:Synapses / Q000473:pathology / Q000502:physiology*; D016896:Treatment Outcome
chemical_list: D000073883:CX3C Chemokine Receptor 1; C471885:Cx3cr1 protein, mouse; D019707:Receptors, Chemokine
keywords: CX3CR1; inflammation; macrophages; microglia; plasticity; spinal cord injury