Reduced inflammation accompanies diminished myelin damage and repair in the NG2 null mouse spinal cord

Abstract

BackgroundMultiple sclerosis (MS) is a demyelinating disease in which blood-derived immune cells and activated microglia damage myelin in the central nervous system. While oligodendrocyte progenitor cells (OPCs) are essential for generating oligodendrocytes for myelin repair, other cell types also participate in the damage and repair processes. The NG2 proteoglycan is expressed by OPCs, pericytes, and macrophages/microglia. In this report we investigate the effects of NG2 on these cell types during spinal cord demyelination/remyelination.MethodsDemyelinated lesions were created by microinjecting 1% lysolecithin into the lumbar spinal cord. Following demyelination, NG2 expression patterns in wild type mice were studied via immunostaining. Immunolabeling was also used in wild type and NG2 null mice to compare the extent of myelin damage, the kinetics of myelin repair, and the respective responses of OPCs, pericytes, and macrophages/microglia. Cell proliferation was quantified by studies of BrdU incorporation, and cytokine expression levels were evaluated using qRT-PCR.ResultsThe initial volume of spinal cord demyelination in wild type mice is twice as large as in NG2 null mice. However, over the ensuing 5 weeks there is a 6-fold improvement in myelination in wild type mice, versus only a 2-fold improvement in NG2 null mice. NG2 ablation also results in reduced numbers of each of the three affected cell types. BrdU incorporation studies reveal that reduced cell proliferation is an important factor underlying NG2-dependent decreases in each of the three key cell populations. In addition, NG2 ablation reduces macrophage/microglial cell migration and shifts cytokine expression from a pro-inflammatory to anti-inflammatory phenotype.ConclusionsLoss of NG2 expression leads to decreased proliferation of OPCs, pericytes, and macrophages/microglia, reducing the abundance of all three cell types in demyelinated spinal cord lesions. As a result of these NG2-dependent changes, the course of demyelination and remyelination in NG2 null mice differs from that seen in wild type mice, with both myelin damage and repair being reduced in the NG2 null mouse. These studies identify NG2 as an important factor in regulating myelin processing, suggesting that therapeutic targeting of the proteoglycan might offer a means of manipulating cell behavior in demyelinating diseases.

NG2 proteoglycan-dependent recruitment of tumor macrophages promotes pericyte-endothelial cell interactions required for brain tumor vascularization

“…Similar to the loss of NG2-dependent macrophage infiltration of tumors, we have also reported that NG2 ablation greatly reduces macrophage recruitment to demyelinated lesions in mouse spinal cord, 34 suggesting the generality of NG2 involvement in macrophage mobilization to tissues. In both the demyelination and tumor studies, transplantation of EGFP-positive bone marrow establishes that the myeloid cells in question are primarily macrophages rather than tissue-resident microglia.…”

“…6 We have also reported that NG2 ablation affects the expression of proinflammatory and anti-inflammatory cytokines in a tissue-specific manner. 13,34 Classically-activated M1 macrophages produce proinflammatory cytokines and can have antitumor functions. Conversely, TAMs frequently exhibit an alternatively-activated M2 phenotype, producing anti-inflammatory cytokines that promote tumor growth.…”

Cannabinoid Receptor 2 Suppresses Leukocyte Inflammatory Migration by Modulating the JNK/c-Jun/Alox5 Pathway

“…However, because it is a stressor of the tissue, inflammation must be tightly controlled. Abnormal migration and activation of innate immune cells can also be harmful and has been implicated widely in the progression of many human diseases, such as multiple sclerosis, rheumatoid arthritis, atherosclerosis, and cancer (1)(2)(3)(4)(5). Therefore, systematic identification of molecular pathways that control innate immune cell migration and activation may provide new therapeutic strategies for treating human diseases associated with disordered inflammation.…”

Glial Cell Plasticity During Development and Myelinopathies

“…By 3.67 hpi, we observed mpeg1 + cells with distinct cytoplasmic vacuoles surrounding sox10 + debris (Figure 5-6B). Taken together, our results demonstrate that our focal drug-induced demyelination model in zebrafish recapitulates the professional phagocyte response previously reported in lysolecithin injected mammalian models (Bø et al, 2012;Doring et al, 2015;Kotter et al, 2001;Kucharova et al, 2011;Rawji & Yong, 2013) Tg ( …”