Non-Primate Monocytes - CD14, CD16 - Ziegler-Heitbrock

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

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.