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Journal of Neuroinflammation
Published in: Journal of Neuroinflammation 1/2019

Open Access 01-12-2019 | Central Nervous System Trauma | Research

Peripheral loss of EphA4 ameliorates TBI-induced neuroinflammation and tissue damage

Authors: Elizabeth A. Kowalski, Jiang Chen, Amanda Hazy, Lauren E. Fritsch, Erwin Kristobal Gudenschwager-Basso, Michael Chen, Xia Wang, Yun Qian, Mingjun Zhou, Matthew Byerly, Alicia M. Pickrell, John B. Matson, Irving Coy Allen, Michelle H. Theus

Published in: Journal of Neuroinflammation | Issue 1/2019

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Abstract

Background

The 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.

Methods

Here, 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.

Results

EphA4 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 increased EPHA4 and pro-inflammatory gene expression, which correlates with reduced AKT concurrent with increased brain injury severity in patients.

Conclusions

Overall, these findings implicate EphA4 as a novel mediator of cortical tissue damage and neuroinflammation following TBI.
Appendix
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Metadata
Title
Peripheral loss of EphA4 ameliorates TBI-induced neuroinflammation and tissue damage
Authors
Elizabeth A. Kowalski
Jiang Chen
Amanda Hazy
Lauren E. Fritsch
Erwin Kristobal Gudenschwager-Basso
Michael Chen
Xia Wang
Yun Qian
Mingjun Zhou
Matthew Byerly
Alicia M. Pickrell
John B. Matson
Irving Coy Allen
Michelle H. Theus
Publication date
01-12-2019
Publisher
BioMed Central
Published in
Journal of Neuroinflammation / Issue 1/2019
Electronic ISSN: 1742-2094
DOI
https://doi.org/10.1186/s12974-019-1605-2

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