Investigating the Mechanisms of Paralysis Development and the Sex-Specific Therapeutic Potential of TNFR2 Activation in a rodent model of MS

"Animal models used to study Multiple Sclerosis (MS) pathophysiology are well established and have predominately focused on paralysis or motor deficits as the functional symptom of MS. However, MS patients suffer from a variety of other symptoms which are rarely documented in animal studies, and the mechanism behind these varied MS symptoms remains unexplored. Using a rodent model for MS, experimental autoimmune encephalomyelitis (EAE), I have studied the diverse immune profile between the two most-prominent MS symptoms – chronic neuropathic pain (CNP) and paralysis, within the same cohort of EAE immunized mice. While all mice develop neuropathic pain, only a subset of them also experience paralysis. However, the pain experienced by mice with or without paralysis is comparable between the two groups, irrespective of sex. Further analysis revealed that the progression to paralysis was linked to increased immune cell infiltration in the spinal cord, accompanied by heightened activation of B cells and macrophages/microglia. Tumor necrosis factor is a multifunctional cytokine which is greatly implicated in MS pathophysiology. Previous research has established that activation of the transmembrane TNF (tmTNF)/ Tumor necrosis factor receptor 2 (TNFR2) signaling pathway can be a potential therapeutic for inflammatory disorders such as MS. Here, I have dissected the sex-specific efficacy of TNFR2 activation in alleviating EAE induced CNP and paralysis. Alleviation of CNP by TNFR2 activation was sex-chromosome independent, however, it was dependent on the gonadal hormone, Activin-A, in both sexes. In addition, the alleviation of EAE induced paralysis by TNFR2 activation was found to be sex-chromosome dependent. After TNFR2 activation, mice with XY chromosomes experienced exacerbated motor disease/paralysis severity as compared to mice with XX sex-chromosome complement type; irrespective of sex. These findings highlight the importance of considering symptom and sex-informed approaches for developing efficacious targeted therapies for MS development."

Author

• Gupta, Shruti

Keyword

• EAE
• TNFR2
• Multiple Sclerosis (MS)
• CNP
• Activin-A

Date created

• 2025

Type of Work

• Dissertation

License

• All rights reserved

Rights statement

• In Copyright

GW Unit

• Institute for Biomedical Sciences

Degree

• Ph.D.

Advisor

• Dr. John R. Bethea

Committee Member(s)

• Dr. Bradley Kerr
• Dr. Vsevolod Polotsky
• Dr. Brett Shook
• Dr. Robert Miller
• Dr. Jason Triplett
• Dr. David Mendelowitz

Persistent URL

•  https://scholarspace.library.gwu.edu/etd/1831ck747

Previous Publication Information

• https://doi.org/10.1016/j.brainresbull.2025.111275