Tumor necrosis factor receptor 2 activation elicits sex-specific effects on cortical myelin proteins and functional recovery in a model of multiple sclerosis
Document Type
Journal Article
Publication Date
1-20-2024
Journal
Brain research bulletin
Volume
207
DOI
10.1016/j.brainresbull.2024.110885
Keywords
Experimental autoimmune encephalomyelitis (EAE); Multiple sclerosis (MS); Sex differences; TNF receptor 2 (TNFR2); Tumor necrosis factor (TNF)
Abstract
Multiple sclerosis (MS), a demyelinating autoimmune disease of the central nervous system (CNS), predominately affects females compared to males. Tumor necrosis factor (TNF), a pro-inflammatory cytokine, signaling through TNF receptor 1 contributes to inflammatory disease pathogenesis. In contrast, TNF receptor 2 signaling is neuroprotective. Current anti-TNF MS therapies are shown to be detrimental to patients due to pleiotropic effects on both pro- and anti-inflammatory functions. Using a non-pertussis toxin (nPTX) experimental autoimmune encephalomyelitis (EAE) model in C57BL/6 mice, we systemically administered a TNFR2 agonist (p53-sc-mTNF) to investigate behavioral and pathophysiological changes in both female and male mice. Our data shows that TNFR2 activation alleviates motor and sensory symptoms in females. However, in males, the agonist only alleviates sensory symptoms and not motor. nPTX EAE induction in TNFR2 global knockout mice caused exacerbated motor symptoms in females along with an earlier day of onset, but not in males. Our data demonstrates that TNFR2 agonist efficacy is sex-specific for alleviation of motor symptoms, however, it effectively reduces mechanical hypersensitivity in both females and males. Altogether, these data support the therapeutic promise TNFR2 agonism holds as an MS therapeutic and, more broadly, to treat central neuropathic pain.
APA Citation
Nguyen, Kayla L.; Bhatt, Ishaan J.; Gupta, Shruti; Showkat, Nazaf; Swanson, Kathryn A.; Fischer, Roman; Kontermann, Roland E.; Pfizenmaier, Klaus; Bracchi-Ricard, Valerie; and Bethea, John R., "Tumor necrosis factor receptor 2 activation elicits sex-specific effects on cortical myelin proteins and functional recovery in a model of multiple sclerosis" (2024). GW Authored Works. Paper 4147.
https://hsrc.himmelfarb.gwu.edu/gwhpubs/4147
Department
Anatomy and Regenerative Biology