Abstract
BackgroundThe G protein-coupled receptor EBI2 (Epstein-Barr virus-induced gene 2) is activated by 7α, 25-dihydroxycholesterol (7α25HC) and plays a role in T cell-dependant antibody response and B cell migration. Abnormal EBI2 signaling is implicated in a range of autoimmune disorders; however, its role in the CNS remains poorly understood.MethodsHere we characterize the role of EBI2 in myelination under normal and pathophysiological conditions using organotypic cerebellar slice cultures and EBI2 knock-out (KO) animals.ResultsWe find that MBP expression in brains taken from EBI2 KO mice is delayed compared to those taken from wild type (WT) mice. In agreement with these in vivo findings, we show that antagonism of EBI2 reduces MBP expression in vitro. Importantly, we demonstrate that EBI2 activation attenuates lysolecithin (LPC)-induced demyelination in mouse organotypic slice cultures. Moreover, EBI2 activation also inhibits LPC-mediated release of pro-inflammatory cytokines such as IL6 and IL1β in cerebellar slices.ConclusionsThese results, for the first time, display a role for EBI2 in myelin development and protection from demyelination under pathophysiological conditions and suggest that modulation of this receptor may be beneficial in neuroinflammatory and demyelinating disorders such as multiple sclerosis.
Highlights
The G protein-coupled receptor EBI2 (Epstein-Barr virus-induced gene 2) is activated by 7α, 25-dihydroxycholesterol (7α25HC) and plays a role in T cell-dependant antibody response and B cell migration
Organotypic cerebellar slices maintain host tissue cytoarchitecture and physiology The cytoarchitecture of cerebellar tissue in organotypic slices prepared from postnatal day 10 (P10) mice and cultured for 14 days in vitro (14 DIV) was investigated with immunocytochemistry
The data showed that CNS resident cells including neurons (Fig. 1 b), astrocytes (Fig. 1 a), microglia/macrophages (Fig. 1 c), and oligodendrocytes (Fig. 1 b) were present in the slices after 14 DIV
Summary
The G protein-coupled receptor EBI2 (Epstein-Barr virus-induced gene 2) is activated by 7α, 25-dihydroxycholesterol (7α25HC) and plays a role in T cell-dependant antibody response and B cell migration. Oxysterols enhance expression and activity of phospholipase A2 leading to a protective effect in oligodendrocytes [10] These studies show that oxysterols may play dual role in oligodendrocyte/CNS biology having either detrimental or supportive functions depending on the oxysterol [10]. A study has shown that treatment of mouse astrocytes with LPS induces the release of 25HC, 7α25HC, and 7β25HC from these cells [6] This LPS-conditioned media induced macrophage migration indicating an important role EBI2/oxysterols axis plays in the crosstalk between the immune and CNS cells. This neurodegenerative disorder belongs to a group of diseases called hereditary spastic paraplegias and is characterized by neuropathy of upper motor neurons as well as periventricular and subcortical white matter lesions [22, 23]
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