Tumor necrosis factor superfamily in multiple sclerosis: from pathology to therapeutic implications

Published: 3 May 2023
Abstract Views: 749
PDF: 84
Publisher's note
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.


  • Federica Azzolini Unit of Neurology, IRCCS Neuromed, Pozzilli, Italy.
  • Antonio Bruno Unit of Neurology, IRCCS Neuromed, Pozzilli, Italy.
  • Ettore Dolcetti Unit of Neurology, IRCCS Neuromed, Pozzilli, Italy.
  • Diego Centonze Unit of Neurology, IRCCS Neuromed, Pozzilli, Italy; Synaptic Immunopathology Lab, Department of Systems Medicine, Tor Vergata University, Rome, Italy.
  • Fabio Buttari Synaptic Immunopathology Lab, Department of Systems Medicine, Tor Vergata University, Rome, Italy.

Tumor necrosis factor (TNF) is a key player in multiple sclerosis pathology. TNF signaling is dually regulated by antagonist groups of actors: TNFR1, mediating proinflammatory effects and synaptopathy, CD40L-CD40 dyad, crucial for blood-brain barrier breakdown and facilitation of recruitment of inflammatory cells in the central nervous system, and TNFR2, promoting neuroprotective and reparative functions. A promising therapeutic approach in multiple sclerosis is represented by selective TNFR1 antagonists and TNFR2 agonists, possibly in combination. TNFR2 agonists could exert both central effects such as remyelination, reduction of glutamatergic excitotoxicity, and peripheral immunomodulation by enhancing T cells (Treg) activity. On the other side, the potential therapeutic role of platelet and CD40L-CD40 dyad inhibition could be beneficial to preserve blood-brain barrier integrity and thereby dampen neuroinflammation.

Fresegna D, Bullitta S, Musella A, et al. Re-examining the role of TNF in MS pathogenesis and therapy. Cells 2020;9:2290. DOI: https://doi.org/10.3390/cells9102290

Dostert C, Grusdat M, Letellier E, Brenner D. The TNF family of ligands and receptors: communication modules in the immune system and beyond. Physiol Rev 2019;99:115-60. DOI: https://doi.org/10.1152/physrev.00045.2017

Probert L. TNF and its receptors in the CNS: the essential, the desirable, and the deleterious effects. Neuroscience 2015;302:2-22. DOI: https://doi.org/10.1016/j.neuroscience.2015.06.038

Aarts SABM, Seijkens TTP, van Dorst KJF, et al. The CD40-CD40L dyad in experimental autoimmune encephalomyelitis and multiple sclerosis. Front Immunol 2017;8:1791. DOI: https://doi.org/10.3389/fimmu.2017.01791

Beattie EC, Stellwagen D, Morishita W, et al. Control of synaptic strength by glial TNFα. Science 2002;295:2282-5. DOI: https://doi.org/10.1126/science.1067859

Saluk-Bijak J, Dziedzic A, Bijak M. Pro-thrombotic activity of blood platelets in multiple sclerosis. Cells 2019;8:110. DOI: https://doi.org/10.3390/cells8020110

Eugster HP, Frei K, Bachmann R, et al. Severity of symptoms and demyelination in MOG-induced EAE depends on TNFR1. Eur J Immunol 1999;29:626-32. DOI: https://doi.org/10.1002/(SICI)1521-4141(199902)29:02<626::AID-IMMU626>3.0.CO;2-A

Gao H, Danzi MC, Choi CS, et al. Opposing functions of microglial and macrophagic TNFR2 in the pathogenesis of experimental autoimmune encephalomyelitis. Cell Rep 2017;18:198-212. DOI: https://doi.org/10.1016/j.celrep.2016.11.083

Karamita M, Barnum C, Möbius W, et al. Therapeutic inhibition of soluble brain TNF promotes remyelination by increasing myelin phagocytosis by microglia. JCI Insight 2017;2:e87455. DOI: https://doi.org/10.1172/jci.insight.87455

Zeitelhofer M, Adzemovic MZ, Moessinger C, et al. Blocking PDGF-CC signaling ameliorates multiple sclerosis-like neuroinflammation by inhibiting disruption of the blood–brain barrier. SciRep 2020;10:22383. DOI: https://doi.org/10.1038/s41598-020-79598-z

Vogelsang A, Eichler S, Huntemann N, et al. Platelet inhibition by low-dose acetylsalicylic acid reduces neuroinflammation in an animal model of multiple sclerosis. Int J Mol Sci 2021;22:9915. DOI: https://doi.org/10.3390/ijms22189915

Ribeiro CM, Oliveira SR, Alfieri DF, et al. Tumor necrosis factor alpha (TNF-α) and its soluble receptors are associated with disability, disability progression and clinical forms of multiple sclerosis. Inflamm Res 2019;68:1049-59. DOI: https://doi.org/10.1007/s00011-019-01286-0

Sharief MK, Hentges R. Association between tumor necrosis factor-α and disease progression in patients with multiple sclerosis. N Engl J Med 1991;325:467-72. DOI: https://doi.org/10.1056/NEJM199108153250704

Shi N, Kawano Y, Matsuoka T, et al. Increase of CD4+TNFα+IL-2-T cells in cerebrospinal fluid of multiple sclerosis patients. Mult Scler 2009;120-3. DOI: https://doi.org/10.1177/1352458508096871

Gentile A, De Vito F, Fresegna D, et al. Peripheral T cells from multiple sclerosis patients trigger synaptotoxic alterations in central neurons. Neuropathol Appl Neurobiol 2020;46:160-70. DOI: https://doi.org/10.1111/nan.12569

Azzolini, F., Bruno, A., Dolcetti, E., Centonze, D., & Buttari, F. (2023). Tumor necrosis factor superfamily in multiple sclerosis: from pathology to therapeutic implications. Bleeding, Thrombosis, and Vascular Biology, 2(2). https://doi.org/10.4081/btvb.2023.66


Download data is not yet available.