Full text

Turn on search term navigation

© 2022. This work is published under https://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.

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.

Details

Title
Monocyte proinflammatory phenotypic control by ephrin type A receptor 4 mediates neural tissue damage
Author
Kowalski, Elizabeth A; Soliman, Eman; Kelly, Colin; Erwin Kristobal Gudenschwager Basso; Leonard, John; Pridham, Kevin J; Ju, Jing; Cash, Alison; Hazy, Amanda; de Jager, Caroline; Kaloss, Alexandra M; Ding, Hanzhang; Hernandez, Raymundo D; Coleman, Gabe; Wang, Xia; Olsen, Michelle L; Pickrell, Alicia M; Theus, Michelle H
Section
Research Articles
Publication year
2022
Publication date
Aug 2022
Publisher
American Society for Clinical Investigation
e-ISSN
23793708
Source type
Scholarly Journal
Language of publication
English
ProQuest document ID
3255722150
Copyright
© 2022. This work is published under https://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.