SELECTIVE TNF RECEPTOR 2 ACTIVATION ALLEVIATES INFLAMMATION AND NEUROLOGICAL DEFICITS IN MULTIPLE SCLEROSIS

Multiple sclerosis (MS) is an autoimmune disease of the central nervous system (CNS) characterized by demyelination, inflammation, and axonal damage in both white and gray matter. Current therapeutic strategies focus on modulating certain immune responses but provide only partial and temporary relief.
Numerous studies have implicated the pro-inflammatory cytokine tumor necrosis factor-α (TNF-α) in MS, as elevated levels are found in active lesions and correlate with disease severity. While TNF- inhibitors are effective in treating other autoimmune diseases like rheumatoid arthritis, their use in MS patients exacerbated symptoms in clinical trials. This may be due to the opposing roles of TNF-α receptors: TNF receptor 1 (TNFR1) promotes inflammation and apoptosis, whereas TNF receptor 2 (TNFR2) supports neuroprotection and tissue regeneration. Thus, selective activation of TNFR2 emerges as a promising therapeutic strategy.
In this study, we used the experimental autoimmune encephalomyelitis (EAE) mouse model of MS, which replicates key disease features, including progressive hind-limb paralysis, axonal demyelination, and immune cell infiltration. Mice were treated with a novel TNFR2 agonist to assess its therapeutic potential in ameliorating MS-related pathology. Our results demonstrate that systemic administration of the TNFR2 agonist significantly improved motor function and alleviated mechanical allodynia. Moreover, inflammation and demyelination were significantly reduced in the CNS of treated animals.
Altogether, these findings suggest that TNFR2 activation may represent a viable therapeutic approach for MS.