Astrocyte-specific expression of interleukin 23 leads to an aggravated phenotype and enhanced inflammatory response with B cell accumulation in the EAE model.
Astrocyte-specific expression of interleukin 23 leads to an aggravated phenotype and enhanced inflammatory response with B cell accumulation in the EAE model.pdf
[en] BACKGROUND: Interleukin 23 is a critical cytokine in the pathogenesis of multiple sclerosis. But the local impact of interleukin 23 on the course of neuroinflammation is still not well defined. To further characterize the effect of interleukin 23 on CNS inflammation, we recently described a transgenic mouse model with astrocyte-specific expression of interleukin 23 (GF-IL23 mice). The GF-IL23 mice spontaneously develop a progressive ataxic phenotype with cerebellar tissue destruction and inflammatory infiltrates with high amounts of B cells most prominent in the subarachnoid and perivascular space.
METHODS: To further elucidate the local impact of the CNS-specific interleukin 23 synthesis in autoimmune neuroinflammation, we induced a MOG35-55 experimental autoimmune encephalomyelitis (EAE) in GF-IL23 mice and WT mice and analyzed the mice by histology, flow cytometry, and transcriptome analysis.
RESULTS: We were able to demonstrate that local interleukin 23 production in the CNS leads to aggravation and chronification of the EAE course with a severe paraparesis and an ataxic phenotype. Moreover, enhanced multilocular neuroinflammation was present not only in the spinal cord, but also in the forebrain, brainstem, and predominantly in the cerebellum accompanied by persisting demyelination. Thereby, interleukin 23 creates a pronounced proinflammatory response with accumulation of leukocytes, in particular B cells, CD4+ cells, but also γδ T cells and activated microglia/macrophages. Furthermore, transcriptome analysis revealed an enhanced proinflammatory cytokine milieu with upregulation of lymphocyte activation markers, co-stimulatory markers, chemokines, and components of the complement system.
CONCLUSION: Taken together, the GF-IL23 model allowed a further breakdown of the different mechanisms how IL-23 drives neuroinflammation in the EAE model and proved to be a useful tool to further dissect the impact of interleukin 23 on neuroinflammatory models.
Disciplines :
Neurology
Author, co-author :
Nitsch, Louisa ✱; Department of Neurology, University Clinic Bonn, Campus Venusberg 1, D-53127, Bonn, Germany. Louisa.Nitsch@ukb.uni-bonn.de
Petzinna, Simon ✱; Department of Neurology, University Clinic Bonn, Campus Venusberg 1, D-53127, Bonn, Germany
Zimmermann, Julian; Department of Neurology, University Clinic Bonn, Campus Venusberg 1, D-53127, Bonn, Germany
Schneider, Linda; Department of Neurology, University Clinic Bonn, Campus Venusberg 1, D-53127, Bonn, Germany ; Department of Surgery, University Clinic Bonn, Campus Venusberg 1, D-53127, Bonn, Germany
Krauthausen, Marius; Department of Neurology, University Clinic Bonn, Campus Venusberg 1, D-53127, Bonn, Germany
HENEKA, Michael ; Department of Neurodegenerative Disease and Geriatric Psychiatry, University Clinic Bonn, Campus Venusberg 1, D-53127, Bonn, Germany
Getts, Daniel R; Department of Microbiology-Immunology and Interdepartmental Immunobiology Center, Northwestern University Feinberg School of Medicine, Chicago, USA
Becker, Albert; Department of Neuropathology, University Clinic Bonn, Campus Venusberg 1, D-53127, Bonn, Germany
Müller, Marcus; Department of Neurology, University Clinic Bonn, Campus Venusberg 1, D-53127, Bonn, Germany ; School of Molecular Bioscience, University of Sydney, Sydney, Australia
✱ These authors have contributed equally to this work.
External co-authors :
yes
Language :
English
Title :
Astrocyte-specific expression of interleukin 23 leads to an aggravated phenotype and enhanced inflammatory response with B cell accumulation in the EAE model.
Deutsche Forschungsgemeinschaft University of Muenster Medical School University of Bonn Medical School Novartis Pharma Universitätsklinikum Bonn
Funding text :
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. JZ was funded by the fund “Bonfor” from the University of Bonn Medical School, Germany and the DFG [KFO177, University of Bonn]. SP was funded by the fund “Bonfor” of the Bonn Medical School, Germany. LN was funded by the DFG [KFO177, University of Bonn] and the “Oppenheim Foerderpreis” Novartis GmbH. Open Access funding enabled and organized by Projekt DEAL.
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