10.4081/btvb.2023.66
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.
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Fabio Buttari
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Bleeding, Thrombosis and Vascular Biology
TNFR2
Tumor necrosis factor superfamily in multiple sclerosis: from pathology to therapeutic implications
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Fabio Buttari
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10.4081/btvb.2023.66
Synaptic Immunopathology Lab, Department of Systems Medicine, Tor Vergata University, Rome
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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.
Tumor necrosis factor superfamily in multiple sclerosis: from pathology to therapeutic implications
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                                                                                                                    MINI-REVIEW
Correspondence: Diego Centonze, Unit of Neurology, IRCCS Neu-
romed, via Atinense 18, 86077 Pozzilli (IS), Italy.
                                                                           Tumor necrosis factor superfamily
Tel.: +39 0865 929250.                                                     in multiple sclerosis: from pathology
E-mail: centonze@uniroma2.it, diego.centonze@neuromed.it
                                                                           to therapeutic implications
Citation: Azzolini F, Bruno A, Dolcetti E, et al. Tumor necrosis
factor superfamily in multiple sclerosis: from pathology to thera-
peutic implications. Bleeding, Thrombosis, and Vascular Biology            Federica Azzolini,1 Antonio Bruno,1 Ettore Dolcetti,1
2023;2:66.                                                                 Diego Centonze,1,2 Fabio Buttari1,2

Key words: TNF; multiple sclerosis; synaptopathy; TNFR1;                   1
                                                                            Unit of Neurology, IRCCS Neuromed, Pozzilli; 2Synaptic
TNFR2.                                                                     Immunopathology Lab, Department of Systems Medicine, Tor
                                                                           Vergata University, Rome, Italy
Contributions: DC, FA, conceptualization; FB, FA, methodology,
writing, original draft preparation; AB, ED, DC, resources; DC,
writing, review and editing, project administration. All authors
have read and agreed to the published version of the manuscript.
                                                                           ABSTRACT
Conflict of interest: the authors declare the following potential con-          Tumor necrosis factor (TNF) is a key player in multiple scle-
flicts of interest for the research, authorship, and/or publication of     rosis pathology. TNF signaling is dually regulated by antagonist
this article. FB acted as an advisory board member of Teva and             groups of actors: TNFR1, mediating proinflammatory effects and
                                                                           synaptopathy, CD40L-CD40 dyad, crucial for blood-brain barrier




                                                                                             ly
Roche and received honoraria for speaking or consultation fees
from Merck Serono, Teva, Biogen Idec, Sanofi, and Novartis and             breakdown and facilitation of recruitment of inflammatory cells




                                                                                     on
non-financial support from Merck Serono, Teva, Biogen Idec, and            in the central nervous system, and TNFR2, promoting neuropro-
Sanofi. DC is an advisory board member of Almirall, Bayer Scher-           tective and reparative functions. A promising therapeutic ap-
ing, Biogen, GW Pharmaceuticals, Merck Serono, Novartis,                   proach in multiple sclerosis is represented by selective TNFR1
Roche, Sanofi-Genzyme, and Teva and received honoraria for




                                                                               e
                                                                           antagonists and TNFR2 agonists, possibly in combination.
speaking or consultation fees from Almirall, Bayer Schering, Bio-
                                                                           TNFR2 agonists could exert both central effects such as remyeli-
gen, GW Pharmaceuticals, Merck Serono, Novartis, Roche, Sanofi-
Genzyme, and Teva. He is also the principal investigator in clinical
trials for Bayer Schering, Biogen, Merck Serono, Mitsubishi, No-
                                                                          us
                                                                           nation, 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-
                                                                          al
vartis, Roche, Sanofi-Genzyme, and Teva. His preclinical and clin-
ical research was supported by grants from Bayer Schering, Biogen          CD40 dyad inhibition could be beneficial to preserve blood-brain
                                                       ci

Idec, Celgene, Merck Serono, Novartis, Roche, Sanofi-Genzyme,              barrier integrity and thereby dampen neuroinflammation.
and Teva. The funders had no role in the design of the study; in the
                                                     er


collection, analyses, or interpretation of data; in the writing of the
manuscript, or in the decision to publish the results. FA, AB, and
                                                    m



ED declare that the research was conducted in the absence of any           INTRODUCTION
commercial or financial relationships that could be construed as a
                                        om




potential conflict of interest.                                                Multiple sclerosis (MS) is a neuroimmunological dis-
                                                                           ease affecting mainly young adults. Cytokines dysregu-
Funding: none.
                                                                           lation plays a relevant role in MS pathology. One major
                                  -c




Ethics approval and consent to participate not applicable.                 actor is the tumor necrosis factor (TNF), a pleiotropic cy-
                         on




                                                                           tokine involved in many physiological and pathological
Acknowledgments: this manuscript is based on an invited presen-
                                                                           functions both in the immune system and in the central
tation at the 9th Roberto Lorenzet Memorial “L’infiammazione base
                                                                           nervous system (CNS). In MS, TNF could alternatively
                   N




comune delle malattie cronico-degenerative”, held on January 13,
2023 - Pozzilli (IS, Italy).                                               play neuroinflammatory or neuroprotective effects due to
                                                                           the high complexity of its signaling pathways and the
Received: 8 March 2023.
                                                                           presence of specific interactions with other cytokines,
Accepted: 14 April 2023.
                                                                           CNS cells, or immune cells.1
Publisher’s note: all claims expressed in this article are solely those
of the authors and do not necessarily represent those of their affili-
ated organizations, or those of the publisher, the editors and the re-
                                                                           TUMOR NECROSIS FACTOR SUPERFAMILY
viewers. Any product that may be evaluated in this article or claim
that may be made by its manufacturer is not guaranteed or endorsed         AND BIOLOGICAL FUNCTION
by the publisher.
                                                                               TNF is the prototype of the TNF superfamily, exerting
©
 Copyright: the Author(s), 2023                                            several biological functions. There are two distinct sur-
Licensee PAGEPress, Italy                                                  face TNF receptors (TNFR): the TNFR superfamily
Bleeding, Thrombosis and Vascular Biology 2023; 2:66                       member 1A (TNFR1) and TNFR superfamily member
doi:10.4081/btvb.2023.66
                                                                           type 2 (TNFR2).2 TNFR1 and TNFR2 play opposite im-
This work is licensed under a Creative Commons Attribution-                munological functions. TNFR1, which is widely ex-
NonCommercial 4.0 International License (CC BY-NC 4.0).                    pressed, plays a role in tissue degeneration and
                                                                           inflammation, while TNFR2 is selectively expressed in

                                            Bleeding, Thrombosis and Vascular Biology 2023; 2:66
44                                                      F. Azzolini et al.




neurons, microglia, oligodendrocytes, T cells, and en-               demonstrating an opposite role of TNFR2 in the periphery
dothelial cells, mediating homeostatic functions.                    versus CNS.
    Another key player of the TNF superfamily is the                     The dual role of TNF is also supported by experimen-
CD40-CD40L dyad, an immune checkpoint regulator.                     tal pharmacological studies. For example, both in EAE
    TNF has a key role in the systemic inflammatory re-              and demyelination cuprizone models, the selective inhi-
sponse, immune surveillance, and immunological home-                 bition of TNFR1 induced milder disease progression, re-
ostasis. Moreover, it regulates many aspects of T cell               duced disease severity and inflammatory infiltrates, lower
biology. TNF-TNFR2 signaling seems to prevail in a sub-              rates of demyelination and axonal damage, and resolved
set of T cells (Treg) that show immunoregulatory func-               microgliosis. According to the hypothesis of an opposite
tions, while TNFR1 is mainly involved in the activation              role of TNFR2 signaling, the potentiation of TNFR2 with
of CD4+ and CD8+ T cell apoptosis and proinflammatory                fusion proteins showed a better disease course in EAE.1
activities. TNFR1 and TNFR2 also play opposite roles in              Moreover, in cuprizone models, TNF-KO mice demyeli-
MS, the first exerting proinflammatory effects, and the              nation was similar to wild-type mice. However, TNFR2-
second neuroprotective and reparative functions.1,3 Sev-             deficient but not TNFR1-deficient mice failed to
eral experimental and pathological studies suggested that            remyelinate compared to wild-type mice.9
the CD40-CD40L activation has a central role in the in-                  Finally, interesting data revealed that the platelet-




                                                                                             ly
flammatory response underlying MS, especially in blood-              CD40L axis could be a potential pharmacological target in




                                                                                      on
brain barrier (BBB) disruption.4                                     MS: both genetic deficiency and antibody-mediated inhi-
    In CNS, TNF is constitutively expressed at low levels            bition of the CD40–CD40L dyad, in fact, reduced disease
and is mainly produced by microglia, astrocytes, and glial           severity in EAE.4 Moreover, intracerebroventricular injec-




                                                                                 e
cells. In a healthy brain, TNF exerts regulatory functions.          tion of platelet-derived growth factor CC (PDGF-CC) in-
Moreover, it acts as a physiological gliotransmitter and
synaptic mediator, as in the regulation of surface expres-
sion of AMPA receptors.5 However, the homeostatic func-
                                                                             us
                                                                     duced upregulation, whereas blocking PDGF-CC during
                                                                     EAE led to downregulation of TNFα and interleukin 1α
                                                                     (IL1A) at the BBB.10 Finally, oral administration of low-
                                                                   al
tions of TNF could turn into pathological effects under              dose acetylsalicylic acid resulted in milder EAE, reduced
proinflammatory conditions.1,3
                                                      ci

                                                                     inflammatory infiltrates, and demyelination.11
                                                                         TNF in MS human post-mortem studies demonstrated
                                                    er


                                                                     higher TNF levels in active MS lesions, with transcrip-
TUMOR NECROSIS FACTOR SUPERFAMILY                                    tional upregulation both of TNFR1 and TNFR2. However,
                                                   m




INVOLVEMENT IN EXPERIMENTAL MODELS                                   a higher expression of TNFR1-mediated necroptosis was
                                          om




AND HUMAN MULTIPLE SCLEROSIS                                         observed, demonstrating the predominance of TNFR1 in
    Experimental animal models showed that the TNFR1                 destructive effects. On the contrary, several studies sug-
pathway can enhance glutamate excitotoxicity, neuroin-               gested that the increased expression of TNFR2 is linked
                                     -c




flammatory response, BBB permeability, and oligoden-                 to reparative effects.1 TNF was also studied in vivo in MS
                                                                     subjects both in serum and in cerebrospinal fluid (CSF)
                             on




drocytes apoptosis.1
    CD40-CD40L dyad also promotes neuroinflamma-                     samples. Higher levels of TNF were found in subjects
tion: soluble CD40L is mainly derived from platelets,                with progressive MS (PMS) with severe disease progres-
                         N




which are also important players in disease pathogenesis.            sion, in primary PMS, in active relapsing-remitting MS
Indeed, MS patients exhibit chronic platelet activation,             (RRMS), while TNF had a negative correlation with cog-
and elevated platelet adhesion is evident during the initial         nitive decline in RRMS.1,12
stage of MS.6 The platelet CD40L-mediated activation of                  Other studies showed that higher CSF TNF concen-
CD40 induces the expression of inflammatory mediators,               trations were associated with neurological deficits and
such as cytokines and chemokines, that enhance BBB dis-              with the degree of disease progression in PMS, whereas
ruption and neuro-inflammation.4                                     serum TNF levels did not reach this association.13 More-
    On the contrary, TNFR2 signaling reduces excitotox-              over, in MS subjects, CD4+TNF+T cells were found at
icity and promotes remyelination in CNS. In experimental             higher concentrations in CSF compared to peripheral
autoimmune encephalitis (EAE) mice models, the selec-                blood.14 These data suggest a specific intrathecal synthesis
tive ablation of TNFR2 in oligodendrocytes induced                   of TNF by autoreactive T cells.
lower remyelination, higher oligodendrocyte loss, in-                    As mentioned before, TNF could exert excitotoxic
creased autoreactive cells infiltrate,1,7 more severe disease        damage in MS, leading to axonal, oligodendroglial, as
course, and increased BBB permeability.1 To notice,                  well as synaptic pathology in MS. In a recent study, for
TNFR2 ablation in peripheral monocytes/macrophages                   example, T cells isolated from the serum of RRMS pa-
resulted in impaired systemic immunity, milder disease               tients and incubated in mice brain slices were able to in-
course, lower demyelination, and CNS T cell infiltration,8           duce synaptic alterations only if derived from MS patients

                                     Bleeding, Thrombosis and Vascular Biology 2023; 2:66
                Tumor necrosis factor superfamily in multiple sclerosis: from pathology to therapeutic implications                45



with active inflammation. In the same model, the coincu-
bation of T cells with a TNF antagonist (etanercept) pre-            REFERENCES
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                                                                          e
CONCLUSIONS                                                              microglial and macrophagic TNFR2 in the pathogenesis of

    TNF is a key player in MS pathology, as confirmed by
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                                                                   us    experimental autoimmune encephalomyelitis. Cell Rep
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                                                                      9. Karamita M, Barnum C, Möbius W, et al. Therapeutic inhi-
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is dually regulated by antagonist groups of actors:                      creasing myelin phagocytosis by microglia. JCI Insight
                                              ci

                                                                         2017;2:e87455.
TNFR1, mediating proinflammatory effects and synap-
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                                            er


topathy, CD40L-CD40 dyad, crucial for BBB breakdown                      ing PDGF-CC signaling ameliorates multiple sclerosis-like
and facilitation of recruitment of inflammatory cells in                 neuroinflammation by inhibiting disruption of the blood–
                                           m




CNS, and TNFR2, promoting neuroprotective and repar-                     brain barrier. SciRep 2020;10:22383.
                                  om




ative functions.                                                     11. Vogelsang A, Eichler S, Huntemann N, et al. Platelet inhibi-
    Therefore, a promising therapeutic approach in MS is                 tion by low-dose acetylsalicylic acid reduces neuroinflam-
represented by the use of selective TNFR1 antagonists                    mation in an animal model of multiple sclerosis. Int J Mol
                             -c




and TNFR2 agonists, possibly in combination. TNFR2                       Sci 2021;22:9915.
                                                                     12. Ribeiro CM, Oliveira SR, Alfieri DF, et al. Tumor necrosis
agonists, interestingly, could exert both central effects
                     on




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                                     Bleeding, Thrombosis and Vascular Biology 2023; 2:66
