ResearchIn-Press PreviewNeuroscience
Open Access | 10.1172/jci.insight.156319
1Department of Biomedical Sciences and Pathobiology, Virginia Tech, Blacksburg, United States of America
2Translational Biology Medicine and Health Graduate Program, Virginia Tech, Blacksburg, United States of America
3School of Neuroscience, Virginia Tech, Blacksburg, United States of America
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1Department of Biomedical Sciences and Pathobiology, Virginia Tech, Blacksburg, United States of America
2Translational Biology Medicine and Health Graduate Program, Virginia Tech, Blacksburg, United States of America
3School of Neuroscience, Virginia Tech, Blacksburg, United States of America
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1Department of Biomedical Sciences and Pathobiology, Virginia Tech, Blacksburg, United States of America
2Translational Biology Medicine and Health Graduate Program, Virginia Tech, Blacksburg, United States of America
3School of Neuroscience, Virginia Tech, Blacksburg, United States of America
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1Department of Biomedical Sciences and Pathobiology, Virginia Tech, Blacksburg, United States of America
2Translational Biology Medicine and Health Graduate Program, Virginia Tech, Blacksburg, United States of America
3School of Neuroscience, Virginia Tech, Blacksburg, United States of America
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1Department of Biomedical Sciences and Pathobiology, Virginia Tech, Blacksburg, United States of America
2Translational Biology Medicine and Health Graduate Program, Virginia Tech, Blacksburg, United States of America
3School of Neuroscience, Virginia Tech, Blacksburg, United States of America
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1Department of Biomedical Sciences and Pathobiology, Virginia Tech, Blacksburg, United States of America
2Translational Biology Medicine and Health Graduate Program, Virginia Tech, Blacksburg, United States of America
3School of Neuroscience, Virginia Tech, Blacksburg, United States of America
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1Department of Biomedical Sciences and Pathobiology, Virginia Tech, Blacksburg, United States of America
2Translational Biology Medicine and Health Graduate Program, Virginia Tech, Blacksburg, United States of America
3School of Neuroscience, Virginia Tech, Blacksburg, United States of America
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Ju, J.
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1Department of Biomedical Sciences and Pathobiology, Virginia Tech, Blacksburg, United States of America
2Translational Biology Medicine and Health Graduate Program, Virginia Tech, Blacksburg, United States of America
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1Department of Biomedical Sciences and Pathobiology, Virginia Tech, Blacksburg, United States of America
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1Department of Biomedical Sciences and Pathobiology, Virginia Tech, Blacksburg, United States of America
2Translational Biology Medicine and Health Graduate Program, Virginia Tech, Blacksburg, United States of America
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1Department of Biomedical Sciences and Pathobiology, Virginia Tech, Blacksburg, United States of America
2Translational Biology Medicine and Health Graduate Program, Virginia Tech, Blacksburg, United States of America
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1Department of Biomedical Sciences and Pathobiology, Virginia Tech, Blacksburg, United States of America
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1Department of Biomedical Sciences and Pathobiology, Virginia Tech, Blacksburg, United States of America
2Translational Biology Medicine and Health Graduate Program, Virginia Tech, Blacksburg, United States of America
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1Department of Biomedical Sciences and Pathobiology, Virginia Tech, Blacksburg, United States of America
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Published June 23, 2022 - More info
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 GFP bone marrow (BM) chimeric approach, we find neuroprotection and lack of significant motor deficits that is marked by reduced monocyte/macrophage cortical infiltration, and increased number of arginase-1-postivity in the absence of BM-derived Epha4. This was accompanied by a shift in monocyte gene profile from pro- to anti-inflammatory that includes increased Tek (Tie2 receptor) expression. Inhibition of Tie2 attenuated enhanced expression of M2-like genes in cultured Epha4-null monocyte/macrophages. In Epha4 BM-deficient mice, cortical-isolated GFP+ monocyte/macrophages displayed a phenotypic shift from 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 wild-type but resulted in attenuation of phenotype in Epha4 BM-deficient mice suggesting control over monocyte polarization not recruitment dictates tissue damage. Thus, coordination of monocyte pro-inflammatory polarization by Epha4 is a key regulatory step mediating neural tissue damage.