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CNS-Specific Synthesis of Interleukin 23 Induces a Progressive Cerebellar Ataxia and the Accumulation of Both T and B Cells in the Brain: Characterization of a Novel Transgenic Mouse Model

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Abstract

Interleukin 23 (IL-23) is a key mediator in neuroinflammation in numerous autoimmune diseases including multiple sclerosis (MS). However, the pathophysiology of IL-23 and how it contributes to neuroinflammation is poorly defined. To further clarify the role of IL-23 in CNS inflammation, we generated a transgenic mouse model (GF-IL23) with astrocyte-targeted expression of both IL-23 subunits, IL-23p19, and IL-23p40. These GF-IL23 mice spontaneously develop a progressive ataxic phenotype, which corresponds to cerebellar tissue destruction, and inflammatory infiltrates most prominent in the subarachnoidal and perivascular space. The CNS-cytokine milieu was characterized by numerous inflammatory mediators such as IL-17a and IFNγ. However, the leukocytic infiltrates were surprisingly predominated by B cells. To further examine the impact of the CNS-specific IL-23 synthesis on an additional systemic inflammatory stimulus, we applied the LPS-induced endotoxemia model. Administration of LPS in GF-IL23 mice resulted in early and pronounced microglial activation, enhanced cytokine production and, in sharp contrast to control animals, in the formation of lymphocytic infiltrates. Our model confirms a critical role for IL-23 in the induction of inflammation in the CNS, in particular facilitating the accumulation of lymphocytes in and around the brain. Thereby, CNS-specific synthesis of IL-23 is able to induce a cascade of inflammatory cytokines leading to microglia activation, astrocytosis, and ultimately tissue damage. The presented transgenic model will be a useful tool to further dissect the role of IL-23 in neuroinflammation.

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Acknowledgments

We thank Marco Hessler for his expert technical assistance. We further thank Jens Reimann for his support in routine histological procedures. MM was a post-doctoral fellow from the Deutsche Forschungsgemeinschaft (DFG, Mu17-07/3-1) and was also supported by the fund ‘Innovative Medical Research’ of the University of Muenster Medical School, Germany. ILC was supported by a start-up grant from the University of Sydney. GCP was supported by grants from the European Union Joint Program, Neurodegenerative Disease Research program (JPND; Horizon 2020 Framework Programme, grant agreement 643417/DACAPO-AD) and a DZNE Intersite grant (DEMDAS 2). JZ was funded by the fund “Bonfor” from the University of Bonn Medical School, Germany and the DFG (KFO177, University of Bonn). LN was funded by the DFG (KFO177, University of Bonn) and the “Oppenheim Foerderpreis” Novartis GmbH.

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Authors and Affiliations

  1. Department of Neurology, Universitaetsklinikum Bonn, Sigmund-Freud-Str. 25, D-53127, Bonn, Germany

    Louisa Nitsch, Julian Zimmermann, Marius Krauthausen, Gabor C. Petzold, Michael T. Heneka & Marcus Müller

  2. School of Life and Environmental Sciences, Marie Bashir Institute for Infectious Diseases and Biosecurity, Charles Perkins Centre, Bosch Institute, The University of Sydney, Sydney, NSW, 2006, Australia

    Markus J. Hofer

  3. German Center for Neurodegenerative Diseases (DZNE), Sigmund-Freud-Str. 27, D-53127, Bonn, Germany

    Raman Saggu & Gabor C. Petzold

  4. Clinical Neuroscience Unit, Universitaetsklinikum Bonn, Bonn, Germany

    Michael T. Heneka

  5. Department of Microbiology-Immunology and Interdepartmental Immunobiology Center, Northwestern University Feinberg School of Medicine, Chicago, IL, USA

    Daniel R. Getts

  6. Department of Neuropathology, Universitaetsklinikum Bonn, Sigmund-Freud-Str. 25, D-53127, Bonn, Germany

    Albert Becker

  7. School of Molecular Bioscience, University of Sydney, Sydney, Australia

    Iain L. Campbell & Marcus Müller

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  1. Louisa Nitsch
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Contributions

Development of the transgenic construct: MM, MJH, ILC. Conceived and designed the experiments: LN, JZ, MK, MM. Performed the experiments: LN, JZ, MK, MM. Analyzed the data: LN, JZ, MK, AB, DG, MM. GCP planned and discussed the MRI experiments. RS developed and optimized the MRI sequences, performed the MRI experiments, analyzed the data, and wrote the MRI methods and results section. Contributed reagents/materials/analysis tools: LN, MTH, ILC, AB, DG, MM. Prepared the manuscript: LN, MM. Corrected and modified the manuscript: all authors.

Corresponding author

Correspondence to Marcus Müller.

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Ethical Approval

All applicable national and institutional guidelines for the care and use of animals were followed. All animal experiments were approved by the Animal Care Commission of Nordrhein-Westfalen.

Conflict of Interest

The authors declare that they have no conflict of interest.

LN and MM received travel grants from Merck, Sanofi Genzyme, TEVA, Novartis GmbH, honoraria for talks and research support from Novartis GmbH.

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Louisa Nitsch and Julian Zimmermann shared authorship

Electronic supplementary material

Figure S1

CNS-specific expression of IL-23 leads to cerebellar infiltrates of the founder mice. The GF-IL23 transgenic founder mice GF-IL23–13 (A), GF-IL23–20 (B), GF-IL23–22 (C), GF-IL23–43 (D) display perivascular and subarachnoidal infiltrates in H&E-staining of the cerebellum. In the founder animals GF-IL23–77 and GF-p19 no infiltrates were observed. Scale bar: 100 μm (PDF 141 kb)

Figure S2

B cell differentiation and activation in GF-IL23 mice Representative flow cytometry profiles profiles of the of single cell suspensions of GF-IL23 mice. (A) CD19+ gated cells of the cerebellum and spleen of GF-IL23 mice were analyzed for CD21 and CD23 expression. We found follicular (CD21intCD23hi) and marginal zone (CD21hiCD23low) B cells. (B) CD45 gated cells of the cerebellum were stained against B220 and CD5 for analysis of a B1 (B220intCD5int) B cell population. (C, D). CD19+ gated cells of GF-IL23 transgenic cerebellum and spleen were analyzed for expression of IgM and IgD, CD19, CD80 and CD86 (C, D). Data are representative for at least n = 6–9 GF-IL23 mice with *p < 0.05. (PDF 58 kb)

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Nitsch, L., Zimmermann, J., Krauthausen, M. et al. CNS-Specific Synthesis of Interleukin 23 Induces a Progressive Cerebellar Ataxia and the Accumulation of Both T and B Cells in the Brain: Characterization of a Novel Transgenic Mouse Model. Mol Neurobiol 56, 7977–7993 (2019). https://doi.org/10.1007/s12035-019-1640-0

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  • DOI: https://doi.org/10.1007/s12035-019-1640-0

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