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Mitochondrial Impairment in Oligodendroglial Cells Induces Cytokine Expression and Signaling

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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 (2–4 days) 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.

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Acknowledgements

The excellent support by Helga Helten, Petra Ibold and Uta Zahn is appreciated. We thank Prof. Dr. Reinhard Windoffer and Dr. Volker Buck for their assistance with confocal microscopy and PD Dr. Claudia Krusche for technical support.

Funding

Grant sponsor: This study was funded by the START program of the medical faculty of the RWTH Aachen University (M.S.).

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Authors and Affiliations

  1. Institute of Neuroanatomy, Faculty of Medicine, RWTH Aachen University, Wendlingweg 2, 52074, Aachen, Germany

    Miriam Scheld, Stella Nyamoya, Adib Zendedel, Cordian Beyer & Tim Clarner

  2. Department of Anatomy and Cell Biology, Faculty of Medicine, RWTH Aachen University, 52074, Aachen, Germany

    Athanassios Fragoulis

  3. Department of Neuroanatomy, Faculty of Medicine, Ludwig-Maximilians-University of Munich, 80336, Munich, Germany

    Stella Nyamoya & Nico Teske

  4. IZKF Genomics Facility, Interdisciplinary Center for Clinical Research, RWTH Aachen University, 52074, Aachen, Germany

    Bernd Denecke

  5. Clinic for Gynaecology and Obstetrics, Faculty of Medicine, RWTH Aachen University, 52074, Aachen, Germany

    Barbara Krauspe

  6. Institute of Anatomy, Faculty of Medicine, University of Rostock, 18057, Rostock, Germany

    Markus Kipp

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  1. Miriam Scheld
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  2. Athanassios Fragoulis
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Correspondence to Miriam Scheld.

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ESM 1

(A) Schematic illustration of the in vitro experimental setup for oligodendroglial cell stimulation and subsequent microglia stimulation with OCM. Oligodendroglial cells (OLN93) were stressed with 10 mM SA for 24 h, medium changed and incubated for 24 h with or without SA to produce OCM-vehicle and OCM-SA, respectively. OCM was then used to stimulate microglia cells for 6 h. (B) Time-line diagram of the 2-d cuprizone feeding in vivo experiments. (C) Signal specificity was validated by incubating slices with the respective secondary antibody without pre-incubation with the first antibody. Results for IL6 and OLIG2 negative controls are shown. Note that no signal was found within the examined tissue regions for any secondary antibody (scale bars 50 μm). Cross reactivity of secondary antibodies with each other or the false primary antibody was additionally excluded (data not shown). (D) Double labeling of IL6 with GFAP and IBA-1 (scale bars 10 μm) shows that also other glial cells than oligodendrocytes are possible sources of IL6 after 2 d cuprizone intoxication. No signal was found in the wildtype negative control (lower row) (scale bars 20 μm). (E) No morphological changes such as an increase in the number of bipolar cells or an increased arborization were found in OCM-SA-stimulated compared to OCM-Veh-stimulated BV2 microglia cells. (F) Shows the gene expression results of arginase 1 and Nos2 (BoxCox-Y transformed) of IL6-stimulated microglia cells (four culture wells, one experiment). LPS stimulation served as a positive control for Nos2 induction. *p < 0.05, vehicle, up H2O (PDF 1494 kb)

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Scheld, M., Fragoulis, A., Nyamoya, S. et al. Mitochondrial Impairment in Oligodendroglial Cells Induces Cytokine Expression and Signaling. J Mol Neurosci 67, 265–275 (2019). https://doi.org/10.1007/s12031-018-1236-6

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