Exogenous activation of tumor necrosis factor receptor 2 promotes recovery from sensory and motor disease in a model of multiple sclerosis.

Abstract

Tumor necrosis factor receptor 2 (TNFR2) is a transmembrane receptor that promotes immune modulation and tissue regeneration and is recognized as a potential therapeutic target for multiple sclerosis (MS). However, TNFR2 also contributes to T effector cell function and macrophage-TNFR2 recently was shown to promote disease development in the experimental autoimmune encephalomyelitis (EAE) model of MS. We here demonstrate that systemic administration of a TNFR2 agonist alleviates peripheral and central inflammation, and reduces demyelination and neurodegeneration, indicating that protective signals induced by TNFR2 exceed potential pathogenic TNFR2-dependent responses. Our behavioral data show that systemic treatment of female EAE mice with a TNFR2 agonist is therapeutic on motor symptoms and promotes long-term recovery from neuropathic pain. Mechanistically, our data indicate that TNFR2 agonist treatment follows a dual mode of action and promotes both suppression of CNS autoimmunity and remyelination. Strategies based on the concept of exogenous activation of TNFR2 therefore hold great promise as a new therapeutic approach to treat motor and sensory disease in MS as well as other inflammatory diseases or neuropathic pain conditions.

• Authors: Roman Fischer, Tanja Padutsch, Valerie Bracchi-Ricard, Kayla L Murphy, George F Martinez, Niky Delguercio, Nicholas Elmer, Maksim Sendetski, Ricarda Diem, Ulrich L M Eisel, Richard J Smeyne, Roland E Kontermann, Klaus Pfizenmaier, John R Bethea
• Journal: Brain, behavior, and immunity (Brain Behav Immun) Vol. 81 Pg. 247-259 (10 2019) ISSN: 1090-2139 [Electronic] Netherlands
• PMID: 31220564 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2019 Elsevier Inc. All rights reserved.

Chemical References

• Receptors, Tumor Necrosis Factor, Type II
• Tumor Necrosis Factor-alpha

Topics

• Animals
• Autoimmunity (immunology)
• Demyelinating Diseases (metabolism)
• Encephalomyelitis, Autoimmune, Experimental (immunology, metabolism, pathology)
• Female
• Inflammation (pathology)
• Macrophages (pathology)
• Mice
• Mice, Inbred C57BL
• Multiple Sclerosis (metabolism, pathology)
• Neuralgia (pathology)
• Neurodegenerative Diseases (metabolism)
• Receptors, Tumor Necrosis Factor, Type II (agonists, metabolism)
• Spinal Cord (pathology)
• T-Lymphocytes, Regulatory (drug effects, immunology, metabolism)
• Tumor Necrosis Factor-alpha (immunology)