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 shortterm cuprizone feeding (2-4 d) 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 supports the view that stressed oligodendrocytes have the potential to activate microglia cells through a specific cocktail of chemokines and cytokines among IL6. IL6. Further studies will have to identify the temporal activation pattern of these signaling molecules, their cellular sources and impact on neuroinflammation.

Neuroinflammation in Bipolar Depression

“…Moreover, stressed oligodendrocytes can also lead to microglia activation through the release of different signaling chemokines and cytokines (51). Microglia activation, as previously reported, has been found in postmortem and in vivo studies of BD patients.…”

Oligodendrocytes modulate the immune-inflammatory response in EAE via TNFR2 signaling

“…This idea is in line with recent observations by Scheld at al. showing that oligodendrocytes exposed to mitochondrial stressors robustly upregulate production of cytokines and chemokines (e.g. IL6) and induce pro-inflammatory activation of microglia (Scheld et al, 2019). We speculate that, after an initial priming by oligodendrocytes, microglia, and possibly astrocytes, take over as master inflammatory/immunomodulatory players and produce the bulk of mediators responsible for attracting immune cells in large numbers into the CNS.…”

Relationship of Iron Metabolism and Short-Term Cuprizone Treatment of C57BL/6 Mice

“…In this time interval no demyelination occurred, but multiple metabolic changes could be observed by other research teams. Lately, Scheld et al proved that after two days of CZ treatment a large IL-6 secretion could be seen by oligodendrocytes in the corpus callosum of the animals [12]. The same elevation of IL-6 expression was noticed in stressed oligodendrocytes, which was accompanied by a similarly high GDF15 mRNA level.…”

“…It has been proven that CZ disrupts energy metabolism of oligodendrocytes and triggers apoptosis [6,10], meanwhile the continuous administration of CZ leads to spontaneous remyelination [11]. The demyelination process due to CZ administration can be followed by monitoring the mRNA levels of IL-6 cytokine and growth/differentiation factor 15 (GDF15), a transcription factor expressed by oligodendrocytes in corpus callosum (CC) [12]. Activation of astrocytes showing a high expression level of glial fibrillary acidic protein (GFAP) is another sign of demyelination [13].…”