Mitochondrial Impairment in Oligodendroglial Cells Induces Cytokine Expression and Signaling.

Abstract

Widespread inflammatory lesions within the central nervous system grey and white matter are major hallmarks of multiple sclerosis. The development of full-blown demyelinating multiple sclerosis lesions might be preceded by preactive lesions which are characterized by focal microglia activation in close spatial relation to apoptotic oligodendrocytes. In this study, we investigated the expression of signaling molecules of oligodendrocytes that might be involved in initial microglia activation during preactive lesion formation. Sodium azide was used to trigger mitochondrial impairment and cellular stress in oligodendroglial cells in vitro. Among various chemokines and cytokines, IL6 was identified as a possible oligodendroglial cell-derived signaling molecule in response to cellular stress. Relevance of this finding for lesion development was further explored in the cuprizone model by applying short-term cuprizone feeding (2-4days) on male C57BL/6 mice and subsequent analysis of gene expression, in situ hybridization and histology. Additionally, we analyzed the possible signaling of stressed oligodendroglial cells in vitro as well as in the cuprizone mouse model. In vitro, conditioned medium of stressed oligodendroglial cells triggered the activation of microglia cells. In cuprizone-fed animals, IL6 expression in oligodendrocytes was found in close vicinity of activated microglia cells. Taken together, our data support the view that stressed oligodendrocytes have the potential to activate microglia cells through a specific cocktail of chemokines and cytokines among IL6. Further studies will have to identify the temporal activation pattern of these signaling molecules, their cellular sources, and impact on neuroinflammation.