Sex-chromosome complement and Activin-A shape the therapeutic potential of TNFR2 activation in a model of MS and CNP

Authors

Shruti Gupta, Department of Anatomy and Cell Biology, The George Washington University, Washington, DC 20052.
Sreejita Arnab, Department of Anatomy and Cell Biology, The George Washington University, Washington, DC 20052.
Kayla L. Nguyen, Department of Anatomy and Cell Biology, The George Washington University, Washington, DC 20052.
Marisa Reed, Department of Cell and Developmental Biology, University of Pennsylvania, Philadelphia, PA 19104.
Payam Fathi, Department of Anatomy and Cell Biology, The George Washington University, Washington, DC 20052.
Kelly Tammen, Department of Anatomy and Cell Biology, The George Washington University, Washington, DC 20052.
Emma Turner, Department of Anatomy and Cell Biology, The George Washington University, Washington, DC 20052.
Erin Jones, Department of Anatomy and Cell Biology, The George Washington University, Washington, DC 20052.
Roman Fischer, Institute of Cell Biology and Immunology, University of Stuttgart, Stuttgart 70569, Germany.
David Mendelowitz, Department of Pharmacology and Physiology, The George Washington University, Washington, DC 20052.
John R. Bethea, Department of Anatomy and Cell Biology, The George Washington University, Washington, DC 20052.

Document Type

Journal Article

Publication Date

5-20-2025

Journal

Proceedings of the National Academy of Sciences of the United States of America

Volume

122

Issue

20

DOI

10.1073/pnas.2426771122

Keywords

Activin-A; multiple sclerosis (MS); neuropathic pain; sex-chromosome complement; tumor necrosis factor receptor 2 (TNFR2)

Abstract

Tumor necrosis factor receptor 2 (TNFR2) activation is a promising-therapeutic strategy for autoimmune disorders such as multiple sclerosis (MS) and chronic neuropathic pain (CNP). This study aimed to identify mechanisms governing the sex-specific efficacy of TNFR2 activation on abrogating pain and motor disease severity in mice experiencing experimental autoimmune encephalomyelitis (EAE), a rodent model of MS. We find that the XX sex-chromosome complement is indispensable for TNFR2-mediated attenuation of EAE-associated motor disease. Mice with XY chromosomes experienced exacerbated motor disease severity, associated with an elevated magnitude of neurodegeneration and demyelination. Contrasting this, we show that TNFR2-mediated alleviation of EAE induced CNP is both sex and sex-chromosome independent. However, the alleviation of CNP following TNFR2 activation across two different neuropathic pain models (EAE and chronic constriction injury) was dependent on the gonadal hormone Activin-A. This suggests a shared mechanism through which gonadal-derived factors impact TNFR2-mediated pain relief, independent of sex hormones. These findings highlight the importance of considering sex chromosomes and sex-independent gonadal hormones in evaluating potential sex-specific differences in drug efficacy during therapeutic development.

APA Citation

Gupta, Shruti; Arnab, Sreejita; Nguyen, Kayla L.; Reed, Marisa; Fathi, Payam; Tammen, Kelly; Turner, Emma; Jones, Erin; Fischer, Roman; Mendelowitz, David; and Bethea, John R., "Sex-chromosome complement and Activin-A shape the therapeutic potential of TNFR2 activation in a model of MS and CNP" (2025). GW Authored Works. Paper 7238.
https://hsrc.himmelfarb.gwu.edu/gwhpubs/7238

Department

Pharmacology and Physiology