Kowalski, Elizabeth A.Soliman, EmanKelly, ColinBasso, Erwin Kristobal GudenschwagerLeonard, JohnPridham, Kevin J.Ju, JingCash, AlisonHazy, Amandade Jager, CarolineKaloss, Alexandra M.Ding, HanzhangHernandez, Raymundo D.Coleman, GabeWang, XiaOlsen, Michelle L.Pickrell, Alicia M.Theus, Michelle H.2022-10-182022-10-182022-08-08e156319http://hdl.handle.net/10919/112195Circulating 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.application/pdfenCreative Commons Attribution 4.0 Internationalbrain-injurymacrophagesexpressionepha4angiogenesisactivationArticle - Refereedhttps://doi.org/10.1172/jci.insight.156319715357374582379-3708