Activation of Inflammatory Response by a Combination of Growth Factors in Cuprizone-Induced Demyelinated Brain Leads to Myelin Repair

Abstract

In vivo remyelination promoted by a combination of four oligodendrocyte specific growth factors (GFs) in cuprizone-induced demyelinated mice brains was described recently by our group. Here we report activation of inflammatory response in mice brain following cuprizone-induced demyelination and its further enhancement immediately after injection of growth factors in vivo, while no significant inflammatory response was evident in GFs-injected normal brains. Cuprizone-induced demyelination was accompanied by increased expression of inflammatory cytokines, TNFalpha and IL-1beta, anti-inflammatory cytokines TGFbeta, IL-10 and increased levels of chemokines, CCL2, CCL5, and CXCL10, produced by resident microglia and astrocytes. During demyelination, involvement of oxidative stress was evident by disruption of mitochondrial structure and temporal decline in reduced glutathione levels, later returning to normal. Increase in the cytokines and chemokines was further enhanced within 2 days post injection (dpi) of GFs, coinciding with signal for repair via activation of pAkt and NFkappaB transcription factor reported earlier. Upregulation of mRNA and protein level of antioxidant genes, metallothionein (MT) I/II and activity of a cytosolic oxidoreductase enzyme, glycerolphosphate-3 dehydrogenase (cGPDH) occurred, resulting in a metabolic shuttle with an increase in glycerol in mice brains during period of demyelination and early GF-mediated repair.

CXCL10 Triggers Early Microglial Activation in the Cuprizone Model

“…Evidence arises that microglia are critically involved in the initiation and progression of a variety of neurodegenerative diseases, among them MS and Alzheimer's disease (112,113). Although increased Cxcl10 expression levels in this model have already been reported by Biancotti et al (81), not much is known about the impact of CXCL10 on microglia function in general and in the cuprizone model in particular. Despite the impact of CXCL10 deficiency on histopathological changes in cuprizone-fed mice, our in vivo results demonstrate effects of CXCL10 on microglia activation status.…”

“…This discrepancy might be due to astrocytic modulation of microglia function in vivo, for example, by the production of ILs such as IL-4 or IL-10 (80, 81). Both ILs have been shown to be induced in cuprizonefed animals (81,82). (84), generates a Th1-favored, proinflammatory response (85), appears to be involved in NK cell recruitment (86), drives plasma cell differentiation (87), and has been linked to the trafficking of immune cells into malignant disease sites (88).…”

Levels of BDNF Impact Oligodendrocyte Lineage Cells following a Cuprizone Lesion

“…For example, pro-inflammatory cytokines, tumor necrosis factor-α (TNF-α and interleukin-1 β (IL-1β,) and anti-inflammatory cytokines, transforming growth factor-β (TGF-β) and interleukin-10 (IL-10) as well as IGF-1 (Mason et al, 2000b; Biancotti et al, 2008) are elevated following cuprizone treatment. Other growth factors, such as PDGF, fibroblast growth factor, and NT-3 remain unchanged (Mason et al, 2000b).…”

A cord blood monocyte–derived cell therapy product accelerates brain remyelination

“…When CPZ is removed from the diet, newly differentiated oligodendrocytes remyelinate the CC over a period of weeks. Astrocytes (35), microglia (11,34,36,37), and infiltrating peripheral monocytes (11,38,39) have been shown to participate in the remyelination process in this model. In this study, we used the immunodeficient NOD/ SCID/IL2Rγ null (NSG) mice that lack functional T cells, B cells, and NK cells and readily accept human tissue grafts (40).…”

“…While oligodendrocytes affect the remyelination of nerve fibers, other cell types are important for this repair process (33). Astrocytes provide trophic factors for oligodendrocytes and also for microglia (35). Microglia also provide trophic factors and remove myelin debris that inhibit remyelination by oligodendrocytes (11,34,36,37).…”