Impact of injury mediators on CNS glia

Multiple Sclerosis (MS) is an inflammatory disorder of the central nervous system (CNS). It is characterized by the infiltration of immune cells into the brain, leading to myelin destruction and the demise of oligodendrocytes (OLs), the myelinating cells of the CNS. The mechanisms of tissue destruction are still being elucidated. We have looked at the effects of two putative injury mediators on resident CNS glia. Firstly, we investigated the functional consequences of signaling via death receptors Fas, DR4 and DR5 and their ligands Fas ligand (FasL) and tumor necrosis factor related apoptosis inducing factor (TRAIL) in astrocytes isolated from fetal CNS and in OLs from human adult brain. We find astrocytes express these receptors but are resistant to apoptosis upon their ligation due to the expression of FLICE inhibitory protein (FLIP). Receptor expression is however not silent as distinct signaling pathways are activated as a result of receptor ligation. In OLs, we find receptor expression can be induced upon upregulation of the stress induced protein p53, at which point OLs become susceptible to FasL and TRAIL killing. In situ in MS lesions displaying oligodendrogliopathy, we demonstrate that a high proportion of OLs are immunopositive for p53, suggesting p53 may play a role in OL demise. Secondly, we investigated the effects of the excitatory amino acid glutamate, acting through ionotropic glutamate receptors, on human adult OLs. Based on animal models, excitotoxicity has been proposed to play a role in OL destruction in MS. We find human OLs are in fact resistant to excitotoxicity mediated by AMPA or kainate receptors and this is in sharp contrast to their rodent counterparts. We propose this resistance is due to the lack of expression of glutamate receptors on human OLs both in vitro and in situ. These results indicate that glutamate is not directly responsible for the killing of otherwise healthy OLs in MS. These studies demonstrate that signaling responses to effector molecules present in MS lesions is cell type specific and is tightly regulated in normal and inflamed brain glia.