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

Autor: Kowalski EA; Department of Biomedical Sciences and Pathobiology, College of Veterinary Medicine, Virginia Tech, Blacksburg, VA, 24061, USA., Chen J; Department of Biomedical Sciences and Pathobiology, College of Veterinary Medicine, Virginia Tech, Blacksburg, VA, 24061, USA., Hazy A; Department of Biomedical Sciences and Pathobiology, College of Veterinary Medicine, Virginia Tech, Blacksburg, VA, 24061, USA., Fritsch LE; Graduate Program in Translational Biology, Medicine, and Health, Virginia Tech, Blacksburg, VA, 24061, USA., Gudenschwager-Basso EK; Department of Biomedical Sciences and Pathobiology, College of Veterinary Medicine, Virginia Tech, Blacksburg, VA, 24061, USA., Chen M; Department of Biomedical Sciences and Pathobiology, College of Veterinary Medicine, Virginia Tech, Blacksburg, VA, 24061, USA., Wang X; Department of Biomedical Sciences and Pathobiology, College of Veterinary Medicine, Virginia Tech, Blacksburg, VA, 24061, USA., Qian Y; Department of Mechanical Engineering, Virginia Tech, Blacksburg, VA, 24061, USA.; Center for Drug Discovery, Virginia Tech, Blacksburg, VA, 24061, USA., Zhou M; Department of Mechanical Engineering, Virginia Tech, Blacksburg, VA, 24061, USA.; Center for Drug Discovery, Virginia Tech, Blacksburg, VA, 24061, USA., Byerly M; Department of Biomedical Sciences and Pathobiology, College of Veterinary Medicine, Virginia Tech, Blacksburg, VA, 24061, USA., Pickrell AM; School of Neuroscience, Virginia Tech, Blacksburg, VA, 24061, USA., Matson JB; Center for Drug Discovery, Virginia Tech, Blacksburg, VA, 24061, USA.; Department of Chemistry, Virginia Tech, Blacksburg, VA, 24061, USA., Allen IC; Department of Biomedical Sciences and Pathobiology, College of Veterinary Medicine, Virginia Tech, Blacksburg, VA, 24061, USA., Theus MH; Department of Biomedical Sciences and Pathobiology, College of Veterinary Medicine, Virginia Tech, Blacksburg, VA, 24061, USA. mtheus@vt.edu.; Graduate Program in Translational Biology, Medicine, and Health, Virginia Tech, Blacksburg, VA, 24061, USA. mtheus@vt.edu.; School of Neuroscience, Virginia Tech, Blacksburg, VA, 24061, USA. mtheus@vt.edu.; Center for Regenerative Medicine, Virginia-Maryland College of Veterinary Medicine, Blacksburg, VA, 24061, USA. mtheus@vt.edu.
Jazyk: angličtina
Zdroj: Journal of neuroinflammation [J Neuroinflammation] 2019 Nov 11; Vol. 16 (1), pp. 210. Date of Electronic Publication: 2019 Nov 11.
DOI: 10.1186/s12974-019-1605-2
Abstrakt: 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. 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.
Databáze: MEDLINE
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