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Dynamic changes and molecular analysis of cell death in the spinal cord of SJL mice infected with the BeAn strain of Theiler’s murine encephalomyelitis virus

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Abstract

Theiler’s murine encephalomyelitis (TME) is caused by the TME virus (TMEV) and represents an important animal model for multiple sclerosis (MS). Oligodendroglial apoptosis and reduced apoptotic elimination of encephalitogenic leukocytes seem to participate in autoimmune demyelination in MS. The present study quantified apoptotic cells in BeAn–TMEV-induced spinal cord white matter lesions at 14, 42, 98, and 196 days post infection (dpi) using immunostaining. Apoptotic cells were identified by transmission electron microscopy and double-immunofluorescence. The mRNA expression of apoptosis-related genes was investigated using microarray analysis. Oligodendroglial apoptosis was already detected in the predemyelinating phase at 14 dpi. Apoptotic cell numbers peaked at 42 dpi and decreased until 196 dpi partly due to reduced T cell apoptosis. In addition to genes involved in the classical pathways of apoptosis induction, microarray analysis detected the expression of genes related to alternative mechanisms of cell death such as pyroptosis, necroptosis, and endoplasmic reticulum stress. Consequently, oligodendroglial apoptosis is involved in the initiation of the TME demyelination process, whereas the development of apoptosis resistance of T cells potentially favors the maintenance of inflammation and myelin loss.

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Acknowledgements

The authors wish to thank Bettina Buck, Petra Grünig, Claudia Herrmann, Kerstin Rohn, Kerstin Schöne, Caroline Schütz, and Danuta Waschke for their excellent technical assistance. Lin Li (File No. 201206170042) and Dandan Li (File No. 201606170128) were supported by grants from the China Scholarship Council. This study was supported by the Deutsche Forschungsgemeinschaft (DFG, BE 4200/3-1) and in part by the Niedersachsen-Research Network on Neuroinfectiology (N-RENNT) of the Ministry of Science and Culture of Lower Saxony, Germany.

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    1. Department of Pathology, University of Veterinary Medicine Hannover, Bünteweg 17, 30559, Hannover, Germany

      Ingo Gerhauser, Lin Li, Dandan Li, Stephanie Klein, Suliman Ahmed Elmarabet, Wolfgang Baumgärtner, Reiner Ulrich & Andreas Beineke

    2. Center for Systems Neuroscience Hannover, Bünteweg 17, 30559, Hannover, Germany

      Wolfgang Baumgärtner, Reiner Ulrich & Andreas Beineke

    3. Department of Non-Clinical Drug Safety, Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach (Riss), Germany

      Ulrich Deschl & Arno Kalkuhl

    4. Department of Experimental Animal Facilities and Biorisk Management, Friedrich-Loeffler-Institut, Greifswald, Insel Riems, Germany

      Reiner Ulrich

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    Ingo Gerhauser, Lin Li, Dandan Li, Reiner Ulrich and Andreas Beineke have contributed equally.

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    Gerhauser, I., Li, L., Li, D. et al. Dynamic changes and molecular analysis of cell death in the spinal cord of SJL mice infected with the BeAn strain of Theiler’s murine encephalomyelitis virus. Apoptosis 23, 170–186 (2018). https://doi.org/10.1007/s10495-018-1448-9

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