Monocyte proinflammatory phenotypic control by ephrin type A receptor 4 mediates neural tissue damage

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dc.contributor.authorKowalski, Elizabeth A.en
dc.contributor.authorSoliman, Emanen
dc.contributor.authorKelly, Colinen
dc.contributor.authorBasso, Erwin Kristobal Gudenschwageren
dc.contributor.authorLeonard, Johnen
dc.contributor.authorPridham, Kevin J.en
dc.contributor.authorJu, Jingen
dc.contributor.authorCash, Alisonen
dc.contributor.authorHazy, Amandaen
dc.contributor.authorde Jager, Carolineen
dc.contributor.authorKaloss, Alexandra M.en
dc.contributor.authorDing, Hanzhangen
dc.contributor.authorHernandez, Raymundo D.en
dc.contributor.authorColeman, Gabeen
dc.contributor.authorWang, Xiaen
dc.contributor.authorOlsen, Michelle L.en
dc.contributor.authorPickrell, Alicia M.en
dc.contributor.authorTheus, Michelle H.en
dc.date.accessioned2022-10-18T19:33:41Zen
dc.date.available2022-10-18T19:33:41Zen
dc.date.issued2022-08-08en
dc.description.abstractCirculating monocytes have emerged as key regulators of the neuroinflammatory milieu in a number of neuropathological disorders. Ephrin type A receptor 4 (Epha4) receptor tyrosine kinase, a prominent axon guidance molecule, has recently been implicated in the regulation of neuroinflammation. Using a mouse model of brain injury and a GFP BM chimeric approach, we found neuroprotection and a lack of significant motor deficits marked by reduced monocyte/macrophage cortical infiltration and an increased number of arginase-1(+) cells in the absence of BM-derived Epha4. This was accompanied by a shift in monocyte gene profile from pro- to antiinflammatory that included increased Tek (Tie2 receptor) expression. Inhibition of Tie2 attenuated enhanced expression of M2-like genes in cultured Epha4-null monocytes/macrophages. In Epha4-BM-deficient mice, cortical-isolated GFP(+) monocytes/macrophages displayed a phenotypic shift from a classical to an intermediate subtype, which displayed reduced Ly6c(hi) concomitant with increased Ly6c(lo)- and Tie2-expressing populations. Furthermore, clodronate liposome-mediated monocyte depletion mimicked these effects in WT mice but resulted in attenuation of phenotype in Epha4-BM-deficient mice. This demonstrates that monocyte polarization not overall recruitment dictates neural tissue damage. Thus, coordination of monocyte proinflammatory phenotypic state by Epha4 is a key regulatory step mediating brain injury.en
dc.description.notesWe acknowledge The Center for Engineered Health for grant support and Mellissa Markus for flow cytometry support. The graphical abstract was created with BioRender.com. This work was supported by National Institute of Neurological Disorders and Stroke of the NIH grants NS121103 (to MHT).en
dc.description.sponsorshipCenter for Engineered Health; National Institute of Neurological Disorders and Stroke of the NIH [NS121103]en
dc.description.versionPublished versionen
dc.format.mimetypeapplication/pdfen
dc.identifier.doihttps://doi.org/10.1172/jci.insight.156319en
dc.identifier.eissn2379-3708en
dc.identifier.issue15en
dc.identifier.othere156319en
dc.identifier.pmid35737458en
dc.identifier.urihttp://hdl.handle.net/10919/112195en
dc.identifier.volume7en
dc.language.isoenen
dc.publisherAmerican Society for Clinical Investigationen
dc.rightsCreative Commons Attribution 4.0 Internationalen
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/en
dc.subjectbrain-injuryen
dc.subjectmacrophagesen
dc.subjectexpressionen
dc.subjectepha4en
dc.subjectangiogenesisen
dc.subjectactivationen
dc.titleMonocyte proinflammatory phenotypic control by ephrin type A receptor 4 mediates neural tissue damageen
dc.title.serialJCI Insighten
dc.typeArticle - Refereeden
dc.type.dcmitypeTexten

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