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ResearchIn-Press PreviewNeuroscience Open Access | 10.1172/jci.insight.156319

Monocyte pro-inflammatory phenotypic control by Ephrin type-A receptor 4 mediates neural tissue damage

Elizabeth A. Kowalski,1 Eman Soliman,1 Colin Kelly,1 Erwin Kristobal Gudenschwager Basso,1 John Leonard,1 Kevin J. Pridham,1 Jing Ju,1 Alison M. Cash,1 Amanda Hazy,1 Caroline de Jager,1 Alexandra M. Kaloss,1 Hanzhang Ding,2 Raymundo D. Hernandez,2 Gabriel M. Coleman,3 Xia Wang,1 Michelle L. Olsen,3 Alicia M. Pickrell,3 and Michelle H. Theus1

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

Find articles by Kowalski, E. in: JCI | PubMed | Google Scholar

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

Find articles by Soliman, E. in: JCI | PubMed | Google Scholar |

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

Find articles by Kelly, C. in: JCI | PubMed | Google Scholar

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

Find articles by Gudenschwager Basso, E. in: JCI | PubMed | Google Scholar

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

Find articles by Leonard, J. in: JCI | PubMed | Google Scholar

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

Find articles by Pridham, K. in: JCI | PubMed | Google Scholar |

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

Find articles by Ju, J. in: JCI | PubMed | Google Scholar |

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

Find articles by Cash, A. in: JCI | PubMed | Google Scholar |

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

Find articles by Hazy, A. in: JCI | PubMed | Google Scholar

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

Find articles by de Jager, C. in: JCI | PubMed | Google Scholar

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

Find articles by Kaloss, A. in: JCI | PubMed | Google Scholar |

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

Find articles by Ding, H. in: JCI | PubMed | Google Scholar |

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

Find articles by Hernandez, R. in: JCI | PubMed | Google Scholar

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

Find articles by Coleman, G. in: JCI | PubMed | Google Scholar

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

Find articles by Wang, X. in: JCI | PubMed | Google Scholar |

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

Find articles by Olsen, M. in: JCI | PubMed | Google Scholar |

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

Find articles by Pickrell, A. in: JCI | PubMed | Google Scholar

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

Find articles by Theus, M. in: JCI | PubMed | Google Scholar |

Published June 23, 2022 - More info

JCI Insight. https://doi.org/10.1172/jci.insight.156319.
Copyright © 2022, Kowalski et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published June 23, 2022 - Version history
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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 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.

Graphical Abstract
graphical abstract
Supplemental material

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Version history
  • Version 1 (June 23, 2022): In-Press Preview
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