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

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dc.contributor.authorKowalski, Elizabeth A.en
dc.contributor.authorChen, Jiangen
dc.contributor.authorHazy, Amandaen
dc.contributor.authorFritsch, Lauren E.en
dc.contributor.authorGudenschwager-Basso, Erwin K.en
dc.contributor.authorChen, Michaelen
dc.contributor.authorWang, Xiaen
dc.contributor.authorQian, Yunen
dc.contributor.authorZhou, Mingjunen
dc.contributor.authorByerly, Matthewen
dc.contributor.authorPickrell, Alicia M.en
dc.contributor.authorMatson, John B.en
dc.contributor.authorAllen, Irving C.en
dc.contributor.authorTheus, Michelle H.en
dc.contributor.departmentMechanical Engineeringen
dc.contributor.departmentBiomedical Sciences and Pathobiologyen
dc.contributor.departmentChemistryen
dc.contributor.departmentSchool of Neuroscienceen
dc.contributor.departmentCenter for Drug Discoveryen
dc.date.accessioned2019-11-18T13:02:47Zen
dc.date.available2019-11-18T13:02:47Zen
dc.date.issued2019-11-11en
dc.date.updated2019-11-17T04:20:07Zen
dc.description.abstractBackground 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.en
dc.description.versionPublished versionen
dc.format.mimetypeapplication/pdfen
dc.identifier.citationJournal of Neuroinflammation. 2019 Nov 11;16(1):210en
dc.identifier.doihttps://doi.org/10.1186/s12974-019-1605-2en
dc.identifier.urihttp://hdl.handle.net/10919/95564en
dc.language.isoenen
dc.rightsCreative Commons Attribution 4.0 Internationalen
dc.rights.holderThe Author(s)en
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/en
dc.titlePeripheral loss of EphA4 ameliorates TBI-induced neuroinflammation and tissue damageen
dc.title.serialJournal of Neuroinflammationen
dc.typeArticle - Refereeden
dc.type.dcmitypeTexten

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