Sequential treatment with a TNFR2 agonist and a TNFR1 antagonist improves outcomes in a humanized mouse model for MS

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J Neuroinflammation. 2023 May 3;20(1):106. doi: 10.1186/s12974-023-02785-y.

Sequential treatment with a TNFR2 agonist and a TNFR1 antagonist improves outcomes in a humanized mouse model for MS

Valentina Pegoretti, Jan Bauer, Roman Fischer, Iskra Paro, Wanda Douwenga, Roland E. Kontermann, Klaus Pfizenmaier, Evelien Houben, Bieke Broux, Niels Hellings, Wia Baron, Jon D. Laman, Ulrich L. M. Eisel

Department of Molecular Neurobiology, Groningen Institute of Evolutionary Life Science (GELIFES), University of Groningen, 9747 AG, Groningen, The Netherlands. Institute of Cell Biology and Immunology, University of Stuttgart, 70569, Stuttgart, Germany. Stuttgart Research Centre Systems Biology, University of Stuttgart, 70569, Stuttgart, Germany. Division of Neuroimmunology, Center for Brain Research, Medical University of Vienna, 1090, Vienna, Austria. Neuroimmune Connections and Repair (NIC&R) Lab, Department of Immunology and Infection, Biomedical Research Institute, Hasselt University, 3590, Hasselt, Belgium. University MS Centre, 3590, Hasselt/Pelt, Belgium. Department Biomedical Sciences of Cells and Systems (BSCS), Section Molecular Neurobiology, University Medical Center Groningen, 9713 GZ, Groningen, The Netherlands. Department Pathology and Medical Biology, University Medical Centre Groningen (UMCG), University of Groningen, 9713 GZ, Groningen, The Netherlands.

Service type: Humanized mice


TNF signaling is an essential regulator of cellular homeostasis. Through its two receptors TNFR1 and TNFR2, soluble versus membrane-bound TNF enable cell death or survival in a variety of cell types. TNF-TNFRs signaling orchestrates important biological functions such as inflammation, neuronal activity as well as tissue de- and regeneration. TNF-TNFRs signaling is a therapeutic target for neurodegenerative diseases such as multiple sclerosis (MS) and Alzheimer's disease (AD), but animal and clinical studies yielded conflicting findings. Here, we ask whether a sequential modulation of TNFR1 and TNFR2 signaling is beneficial in experimental autoimmune encephalomyelitis (EAE), an experimental mouse model that recapitulates inflammatory and demyelinating aspects of MS. To this end, human TNFR1 antagonist and TNFR2 agonist were administered peripherally at different stages of disease development in TNFR-humanized mice. We found that stimulating TNFR2 before onset of symptoms leads to improved response to anti-TNFR1 therapeutic treatment. This sequential treatment was more effective in decreasing paralysis symptoms and demyelination, when compared to single treatments. Interestingly, the frequency of the different immune cell subsets is unaffected by TNFR modulation. Nevertheless, treatment with only a TNFR1 antagonist increases T-cell infiltration in the central nervous system (CNS) and B-cell cuffing at the perivascular sites, whereas a TNFR2 agonist promotes Treg CNS accumulation. Our findings highlight the complicated nature of TNF signaling which requires a timely balance of selective activation and inhibition of TNFRs in order to exert therapeutic effects in the context of CNS autoimmunity.

Keywords: EAE; MS; Neuroinflammation; TNF; TNFR1 antagonist; TNFR2 agonist.

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