Role of NG2 proteoglycan in macrophage recruitment to brain tumors and sites of CNS demyelination.

Abstract

Macrophage infiltration is a factor in most if not all inflammatory pathologies. Understanding molecular interactions that underlie this process is therefore important for our ability to modulate macrophage behavior for therapeutic purposes. Our studies show that cell surface expression of the nerveglial antigen 2 (NG2) proteoglycan is important for the ability of macrophages to colonize both brain tumors and sites of central nervous system (CNS) demyelination. Myeloid-specific ablation of NG2 using LysM-Cre deleter mice results in large decreases in macrophage abundance in both an intracranial melanoma model and a lysolecithin model of spinal cord demyelination. In the melanoma model, decreased macrophage recruitment in the NG2 null mice leads to diminished tumor growth. In line with observations in the literature, this phenomenon is based in part on deficits in tumor vascularization that result from loss of pericyte interaction with endothelial cells in the absence of a macrophage-derived factor(s). In the demyelination model, decreased macrophage infiltration in the NG2 null mice is associated with an initial reduction in lesion size, but nevertheless also with deficits in repair of the lesion. Diminished myelin repair is due not only to reduced clearance of myelin debris, but also to decreased proliferation/recruitment of oligodendrocyte progenitor cells in the absence of a macrophage-derived factor(s). Thus, in both models macrophages have secondary effects on other cell types that are important for progression of the specific pathology. Efforts are underway to identify mechanisms by which NG2 influences macrophage recruitment and by which macrophages signal to other cell types involved in the pathologies.