Time-dependent effects of CX3CR1 in a mouse model of mild traumatic brain injury.
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.


CONCLUSIONS
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.
Department of Anesthesiology and Pain Medicine, University of Washington, BOX # 359724, Seattle, WA, 98001, USA.|Present address: Interdepartmental Program in Neuroscience, University of Utah School of Medicine, Salt Lake City, Utah, USA.
Heidi Y
HY
Febinger
Department of Anesthesiology and Pain Medicine, University of Washington, BOX # 359724, Seattle, WA, 98001, USA.|Neuroscience Graduate Program, University of Washington, Seattle, WA, 98104, USA.
Hannah E
HE
Thomasy
Department of Anesthesiology and Pain Medicine, University of Washington, BOX # 359724, Seattle, WA, 98001, USA.
Maria N
MN
Pavlova
Department of Anesthesiology and Pain Medicine, University of Washington, BOX # 359724, Seattle, WA, 98001, USA.
Kristyn M
KM
Ringgold
Department of Anesthesiology and Pain Medicine, University of Washington, BOX # 359724, Seattle, WA, 98001, USA.
Paulien R
PR
Barf
Department of Anesthesiology and Pain Medicine, University of Washington, BOX # 359724, Seattle, WA, 98001, USA.
Amrita M
AM
George
Department of Anesthesiology and Pain Medicine, University of Washington, BOX # 359724, Seattle, WA, 98001, USA.|Department of Biology, University of Washington, Seattle, WA, 98104, USA.
Jenna N
JN
Grillo
Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY, 40536, USA.
Adam D
AD
Bachstetter
Department of Biology and South Texas Center for Emerging Infectious Diseases, University of Texas at San Antonio, San Antonio, TX, 78249, USA.
Jenny A
JA
Garcia
Department of Biology and South Texas Center for Emerging Infectious Diseases, University of Texas at San Antonio, San Antonio, TX, 78249, USA.
Astrid E
AE
Cardona
Department of Anesthesiology and Pain Medicine, University of Washington, BOX # 359724, Seattle, WA, 98001, USA.
Mark R
MR
Opp
Department of Anesthesiology and Pain Medicine, University of Washington, BOX # 359724, Seattle, WA, 98001, USA. cgemma@u.washington.edu.
Carmelina
C
Gemma
D000704:Analysis of Variance; D000818:Animals; D001921:Brain / Q000473:pathology*; D001930:Brain Injuries / Q000150:complications / Q000378:metabolism / Q000473:pathology; D000073883:CX3C Chemokine Receptor 1; D004195:Disease Models, Animal; D005106:Exploratory Behavior / Q000502:physiology; D005434:Flow Cytometry; D005452:Fluoresceins / Q000378:metabolism; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000473:pathology; D008262:Macrophage Activation / Q000235:genetics / Q000502:physiology; D008297:Male; D018782:Maze Learning / Q000502:physiology; D051379:Mice; D008822:Mice, Transgenic; D009474:Neurons / Q000473:pathology; D011596:Psychomotor Disorders / Q000209:etiology; D019707:Receptors, Chemokine / Q000235:genetics / Q000378:metabolism*; D045442:Rotarod Performance Test; D013997:Time Factors
D000073883:CX3C Chemokine Receptor 1; C471885:Cx3cr1 protein, mouse; D005452:Fluoresceins; D019707:Receptors, Chemokine; C435731:fluoro jade; D049452:Green Fluorescent Proteins