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Monocyte proinflammatory phenotypic control by ephrin type A receptor 4 mediates neural tissue damage
Elizabeth A. Kowalski, … , Alicia M. Pickrell, Michelle H. Theus
Elizabeth A. Kowalski, … , Alicia M. Pickrell, Michelle H. Theus
Published June 23, 2022
Citation Information: JCI Insight. 2022;7(15):e156319. https://doi.org/10.1172/jci.insight.156319.
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Research Article Neuroscience

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

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Abstract

Circulating 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 Ly6chi concomitant with increased Ly6clo- 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.

Authors

Elizabeth A. Kowalski, Eman Soliman, Colin Kelly, Erwin Kristobal Gudenschwager Basso, John Leonard, Kevin J. Pridham, Jing Ju, Alison Cash, Amanda Hazy, Caroline de Jager, Alexandra M. Kaloss, Hanzhang Ding, Raymundo D. Hernandez, Gabe Coleman, Xia Wang, Michelle L. Olsen, Alicia M. Pickrell, Michelle H. Theus

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