2025
J Mol Med (Berl). 2025 May 10. doi: 10.1007/s00109-025-02549-6. Online ahead of print.
Single intracerebroventricular TNFR2 agonist injection impacts remyelination in the cuprizone model
Department of Molecular Neurobiology, Groningen, Institute of Evolutionary Life Science (GELIFES), University of Groningen, Groningen, he Netherlands. Department Biomedical Sciences, Section Molecular Cell Biology, University of Groningen, University Medical Center Groningen (UMCG), Groningen, The Netherlands. Institute of Cell Biology and Immunology, University of Stuttgart, Germany; Stuttgart Research Centre Systems Biology, University of Stuttgart, Stuttgart, Germany. Department Pathology and Medical Biology, University of Groningen, University Medical Center Groningen (UMCG), Groningen, The Netherlands. Department Biomedical Sciences, Section Molecular Neurobiology, University of Groningen, University Medical Center Groningen (UMCG), MS Center Noord Nederland (MSCNN), A. Deusinglaan 1, 9713 AV, Groningen, The Netherlands
Service type: Knock-in mice
Abstract
The development of therapeutics that enhances the regeneration of myelin sheaths following demyelination is predicted to prevent neurodegeneration. A promising target to enhance remyelination is the immunomodulatory cytokine tumor necrosis factor alpha (TNFα) and its receptors TNFR1 and TNFR2. TNFR2 on oligodendrocyte lineage cells and microglia coordinates different protective functions, such as proliferation of oligodendrocyte progenitor cells, survival of mature oligodendrocytes, and release of anti-inflammatory cytokines, in animal models of inflammation and demyelination. Here, we find in the cuprizone model that following demyelination, fewer axons are unmyelinated in the corpus callosum at an early stage of remyelination after single TNFR2 agonist delivery in the lateral ventricle, while astrocyte and microglia number and coverage are unchanged. Towards later stages of remyelination, TNFR2 agonist treatment maintains the number of oligodendrocyte lineage cells, and large caliber axons have thinner myelin. Hence, even short-term stimulation of TNFR2 has a positive impact on the remyelination processes. This study informs further on the beneficial implications of TNFR2 signaling on oligodendrocyte lineage cells and remyelination, emphasizing its potential therapeutic value for demyelinating diseases, including multiple sclerosis. KEY MESSAGES: Single TNFR2 agonist treatment in the lateral ventricle following cuprizone-induced demyelination impacts remyelination by: Leading to a lower percentage of unmyelinated axons at early stages. Preserving the number of oligodendrocyte lineage cells in the corpus callosum at later stages. Covering large calibre axons with thinner myelin sheaths at later stages. Keywords: Cuprizone model; Multiple sclerosis; Nanotomy; Oligodendrocyte lineage cells; Remyelination; Tumor necrosis factor receptor 2.
View Publication