Abstract
We used a bone marrow transplantation approach to distinguish the activities of bone marrow-derived macrophages from the activities of central nervous system-resident microglia in phenomena associated with axon demyelination and remyelination. We transplanted wild type or germline NG2 null beta-actin-EGFP expressing bone marrow into irradiated wild type or NG2 null recipient mice, followed by analysis of lysolecithin-induced spinal cord demyelination and remyelination and quantification of Iba-1+/ F4/80+/ EGFP+ macrophages and Iba-1+/ F4/80+/ EGFP- microglia. One week after microinjection of 1% lysolecithin into the spinal cord, wild type recipients receiving NG2 null bone marrow exhibit greatly reduced infiltration of macrophages into lesions, compared to wild type recipients receiving wild type bone marrow. Wild type bone marrow recipients also exhibit larger numbers of demyelinated axons than NG2 null recipients, indicative of macrophage participation in the initial myelin damage. However, wild type bone marrow recipients also exhibit superior myelin repair at 6 weeks post-injury, compared to NG2 null bone marrow recipients, demonstrating the additional importance of macrophages in remyelination. Incompletely repaired lesions in NG2 null bone marrow recipients at 6 weeks post-injury retain elevated numbers of macrophages, in contrast to lower numbers of macrophages in more completely repaired lesions in wild type bone marrow recipients. This suggests that NG2 expression renders macrophages more effective in myelin repair and less likely to promote chronic inflammation. Effective macrophage involvement in myelin repair is due in part to effects on the proliferation and/or recruitment of oligodendrocyte progenitor cells. Reduced numbers of oligodendrocyte progenitors are seen in lesions in NG2 null bone marrow recipients, likely due to deficits in macrophage production of oligodendrocyte progenitor-relevant mitogens and in phagocytosis of inhibitory myelin debris. Microglia also appear to be important for clearance of myelin debris, as indicated by reduced phagocytosis in NG2 null recipients receiving wild type bone marrow.
Highlights
The pathology of multiple sclerosis (MS) is complex due at least in part to the participation of several different cell types in disease progression [1,2,3,4,5,6]
Did not allow us to distinguish between macrophage versus microglial activities, due to LysM-Cre mediated ablation in both cell types, or to determine with certainty how effectively NG2 was ablated in myeloid cells, due to the transience of NG2 expression in those cells
(2) Ablation of NG2 in macrophages leads to decreased phagocytosis of myelin debris by macrophages, confirming the diminished macrophage phagocytosis of myelin debris observed in My-NG2ko mice
Summary
The pathology of multiple sclerosis (MS) is complex due at least in part to the participation of several different cell types in disease progression [1,2,3,4,5,6]. We have previously shown that the NG2 proteoglycan is expressed by three different populations of cells in demyelinated lesions induced in mouse spinal cord by microinjection of lysolecithin [7, 8]. Oligodendrocyte progenitor cells (OPCs), pericytes, and myeloid cells (macrophages and microglia) all contribute to NG2 expression in these lesions. Using Cre-Lox technology, we have ablated NG2 in two of these populations, OPCs and myeloid cells [8]. This has led to initial understanding of NG2 function in these cell types, and to the generation of mouse models characterized by reduced participation of OPCs and myeloid cells in lesion formation and repair
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