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.
[en] 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.
Disciplines :
Neurology
Author, co-author :
Nitsch, Louisa; Department of Neurology, Universitaetsklinikum Bonn, Sigmund-Freud-Str. 25, D-53127, Bonn, Germany
Zimmermann, Julian; Department of Neurology, Universitaetsklinikum Bonn, Sigmund-Freud-Str. 25, D-53127, Bonn, Germany
Krauthausen, Marius; Department of Neurology, Universitaetsklinikum Bonn, Sigmund-Freud-Str. 25, D-53127, Bonn, Germany
Hofer, Markus J; 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
Saggu, Raman; German Center for Neurodegenerative Diseases (DZNE), Sigmund-Freud-Str. 27, D-53127, Bonn, Germany
Petzold, Gabor C; Department of Neurology, Universitaetsklinikum Bonn, Sigmund-Freud-Str. 25, D-53127, Bonn, Germany ; German Center for Neurodegenerative Diseases (DZNE), Sigmund-Freud-Str. 27, D-53127, Bonn, Germany
HENEKA, Michael ; Department of Neurology, Universitaetsklinikum Bonn, Sigmund-Freud-Str. 25, D-53127, Bonn, Germany ; Clinical Neuroscience Unit, Universitaetsklinikum Bonn, Bonn, Germany
Getts, Daniel R; Department of Microbiology-Immunology and Interdepartmental Immunobiology Center, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
Becker, Albert; Department of Neuropathology, Universitaetsklinikum Bonn, Sigmund-Freud-Str. 25, D-53127, Bonn, Germany
Campbell, Iain L; School of Molecular Bioscience, University of Sydney, Sydney, Australia
Müller, Marcus ; Department of Neurology, Universitaetsklinikum Bonn, Sigmund-Freud-Str. 25, D-53127, Bonn, Germany. marcus_m.mueller@ukb.uni-bonn.de ; School of Molecular Bioscience, University of Sydney, Sydney, Australia. marcus_m.mueller@ukb.uni-bonn.de
External co-authors :
yes
Language :
English
Title :
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.
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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