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

EA Kowalski, J Chen, A Hazy, LE Fritsch… - Journal of …, 2019 - Springer
EA Kowalski, J Chen, A Hazy, LE Fritsch, EK Gudenschwager-Basso, M Chen, X Wang…
Journal of Neuroinflammation, 2019Springer
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 CX3CR1 gfp-positive cells in the peri-lesion …
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.
Springer