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

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...

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Detalles Bibliográficos
Autores principales: Kowalski, Elizabeth A., Soliman, Eman, Kelly, Colin, Basso, Erwin Kristobal Gudenschwager, 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.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Society for Clinical Investigation 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9462496/
https://www.ncbi.nlm.nih.gov/pubmed/35737458
http://dx.doi.org/10.1172/jci.insight.156319
Descripción
Sumario: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 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.