Details

Autor(en) / Beteiligte

• 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

Titel

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

Ist Teil von

• JCI insight, 2022-08, Vol.7 (15)

Ort / Verlag

United States: American Society for Clinical Investigation

Erscheinungsjahr

2022

Link zum Volltext

Quelle

Elektronische Zeitschriftenbibliothek (Open access)

Beschreibungen/Notizen

• 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.