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Toll-Like Receptor 2-Mediated Glial Cell Activation in a Mouse Model of Cuprizone-Induced Demyelination

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Abstract

Multiple sclerosis (MS) is a chronic degenerative disease of the central nervous system that is characterized by myelin abnormalities, oligodendrocyte pathology, and concomitant glia activation. The factors triggering gliosis and demyelination are currently not well characterized. New findings suggest an important role of the innate immune response in the initiation and progression of active demyelinating lesions. Especially during progressive disease, aberrant glia activation rather than the invasion of peripheral immune cells is accountable for progressive neuronal injury. The innate immune response can be induced by pathogen-associated or danger-associated molecular patterns, which are identified by pattern recognition receptors (PRRs), including the Toll-like receptors (TLRs). In this study, we used the cuprizone model in mice to investigate the expression of TLR2 during the course of cuprizone-induced demyelination. In addition, we used TLR2-deficient mice to analyze the functional role of TLR2 activation during cuprizone-induced demyelination and reactive gliosis. We show a significantly increased expression of TLR2 in the corpus callosum and hippocampus of cuprizone-intoxicated mice. The absence of receptor signaling in TLR2-deficient mice resulted in less severe reactive astrogliosis in the corpus callosum and cortex. In addition, microglia activation was ameliorated in the corpus callosum of TLR2-deficient mice, but augmented in the cortex compared to wild-type littermates. Extent of demyelination and loss of mature oligodendrocytes was comparable in both genotypes. These results suggest that the TLR2 orchestrates glia activation during gray and white matter demyelination in the presence of an intact blood-brain barrier. Future studies now have to address the underlying mechanisms of the region-specific TLR2-mediated glia activation.

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Abbreviations

CC:

Corpus callosum

CX:

Cortex

TLR:

Toll-like receptor

GFAP:

Glial fibrillary acidic protein

Hc:

Hippocampus

IBA-1:

Ionized calcium-binding adaptor molecule 1

Itgam:

Integrin alpha M

KO:

Knock out

PLP:

Proteolipid protein

WT:

Wild-type

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Acknowledgements

We thank Susanne Echterhagen and Lian Shen for excellent technical assistance and Adib Zendedel for his help with animal experiments.

Funding

This study was supported by the Else Kröner-Fresenius-Stiftung (LOB) and START-Program of the RWTH Aachen University (LOB).

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Author notes

  1. Stefan Esser and Larissa Göpfrich contributed equally as first authors; Markus Kipp and Lars-Ove Brandenburg contributed equally as senior authors.

Authors and Affiliations

  1. Department of Anatomy and Cell Biology, RWTH Aachen University, Wendlingweg 2, 52074, Aachen, Germany

    Stefan Esser, Larissa Göpfrich, Kai Bihler, Eugenia Kress, Thomas Pufe & Lars-Ove Brandenburg

  2. Institute of Neuroanatomy, RWTH Aachen University, Aachen, Germany

    Stella Nyamoya & Tim Clarner

  3. Department of Neurology, RWTH University Hospital Aachen, Aachen, Germany

    Simone C. Tauber

  4. Department of Urology, University Medicine Greifswald, Greifswald, Germany

    Matthias B. Stope

  5. Department of Anatomy II, Ludwig-Maximilians-University of Munich, Munich, Germany

    Markus Kipp

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  1. Stefan Esser
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Correspondence to Lars-Ove Brandenburg.

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Esser, S., Göpfrich, L., Bihler, K. et al. Toll-Like Receptor 2-Mediated Glial Cell Activation in a Mouse Model of Cuprizone-Induced Demyelination. Mol Neurobiol 55, 6237–6249 (2018). https://doi.org/10.1007/s12035-017-0838-2

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