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Peripheral loss of EphA4 ameliorates TBI-induced neuroinflammation and tissue damage
- Source :
- Journal of Neuroinflammation, Journal of Neuroinflammation, Vol 16, Iss 1, Pp 1-16 (2019)
- Publication Year :
- 2019
-
Abstract
- BackgroundThe continuum of pro- and anti-inflammatory response elicited by traumatic brain injury (TBI) is suggested to play a key role in the outcome of TBI; however, the underlying mechanisms remain ill -defined.MethodsHere, we demonstrate that using bone marrow chimeric mice and systemic inhibition of EphA4 receptor shifts the pro-inflammatory milieu to pro-resolving following acute TBI.ResultsEphA4 expression is increased in the injured cortex as early as 2 h post-TBI and on CX3CR1gfp-positive cells in the peri-lesion. Systemic inhibition or genetic deletion of EphA4 significantly reduced cortical lesion volume and shifted the inflammatory profile of peripheral-derived immune cells to pro-resolving in the damaged cortex. These findings were consistent with in vitro studies showing EphA4 inhibition or deletion altered the inflammatory state of LPS-stimulated monocyte/macrophages towards anti-inflammatory. Phosphoarray analysis revealed that EphA4 may regulate pro-inflammatory gene expression by suppressing the mTOR, Akt, and NF-κB pathways. Our human metadata analysis further demonstrates increasedEPHA4and pro-inflammatory gene expression, which correlates with reduced AKT concurrent with increased brain injury severity in patients.ConclusionsOverall, these findings implicate EphA4 as a novel mediator of cortical tissue damage and neuroinflammation following TBI.
- Subjects :
- 0301 basic medicine
Male
Traumatic brain injury
Endothelial cells
Immunology
Inflammation
Mice, Transgenic
lcsh:RC346-429
03 medical and health sciences
Cellular and Molecular Neuroscience
Mice
0302 clinical medicine
Monocyte/macrophage polarization
Brain Injuries, Traumatic
medicine
Animals
Humans
Interleukin 6
Protein kinase B
Neuroinflammation
PI3K/AKT/mTOR pathway
lcsh:Neurology. Diseases of the nervous system
Cerebral Cortex
biology
business.industry
Interleukin-6
General Neuroscience
Monocyte
Research
Akt
Receptor, EphA4
medicine.disease
Disease Models, Animal
030104 developmental biology
medicine.anatomical_structure
Neurology
Blood-Brain Barrier
Cancer research
biology.protein
Encephalitis
Bone marrow
Microglia
medicine.symptom
business
030217 neurology & neurosurgery
Subjects
Details
- ISSN :
- 17422094
- Volume :
- 16
- Issue :
- 1
- Database :
- OpenAIRE
- Journal :
- Journal of neuroinflammation
- Accession number :
- edsair.doi.dedup.....eadd55530f7a4897f717cbbec27ea260