ArticleProceedings of the National Academy of Sciences of the United States of America2025
Sex-chromosome complement and Activin-A shape the therapeutic potential of TNFR2 activation in a model of MS and CNP.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 5 papers.
What it found
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The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
5 citing papers in PubMed.
- NETs mediate neuropathic pain in PSS-PN by participating in inflammatory injury to the vasa nervorum.Clinical rheumatology · 2026Article
- Understanding the Role of Hypothalamic-Pituitary-Gonadal Axis in Multiple Sclerosis and Experimental Autoimmune Encephalomyelitis.Biomedicines · 2026Review
- TNFR2 Agonism as a Sex-Specific Therapy for Novel Osteoarthritis-Induced Cardiac Dysfunction.bioRxiv : the preprint server for biology · 2026Article
- Advancing EAE Modeling: Establishment of a Non-Pertussis Immunization Protocol for Multiple Sclerosis.Bio-protocol · 2026Article
- TNFR2 signaling shapes the sex-specific remyelinating properties of microglia after experimental stroke.Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics · 2025Article
Corrections and comments
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Authors and funding
11 authors.
Funding
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.
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Registered trials
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