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

• DOI: 10.1172/jci.insight.156319
• Publication Date: 2022-07-21T17:16:11Z
• Authors: Elizabeth A. Kowa...; Eman Soliman; Colin Kelly; Erwin Kristobal G...; John Leonard; Kevin J. Pridham; Jing Ju; Alison Cash; Amanda Hazy; Caroline de Jager; Alexandra M. Kaloss; Hanzhang Ding; Raymundo D. Herna...; Gabe Coleman; Xia Wang; Michelle L. Olsen; Alicia M. Pickrell; Michelle H. Theus
• Keywords: 0301 basic medicine; Receptor, EphB2; R; Monocytes; 3. Good health; Mice; 03 medical and health sciences; Phenotype; Brain Injuries; Medicine; Humans; Animals; Ephrins; Neuroscience; Research Article

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.