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Tumor Necrosis Factor (TNF) in Neurological Disorders

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A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cells of the Nervous System".

Deadline for manuscript submissions: closed (28 February 2021) | Viewed by 35982

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Prof. Roberta Brambilla

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Guest Editor

Department of Neurological Surgery, University of Miami Leonard M. Miller School of Medicine, Miami, FL 33136, USA
Interests: neuroinflammation; glia; multiple sclerosis; spinal cord injury

Prof. Dr. Kate Lykke Lambertsen

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Guest Editor

Department of Neurobiology Research, Institute of Molecular Medicine, University of Southern Denmark, 5000 Odense C, Denmark
Interests: neuroinflammation; microglia; cytokines; stroke; spinal cord injury
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Dear Colleagues,

In recent years, exciting research efforts have highlighted the important role played by the pleiotropic cytokine tumor necrosis factor (TNF) in neurological disease. Studies in patients, as well as animal models, have uncovered that the vast majority of CNS pathologies, whether acute or chronic, are associated with an increased expression of TNF, making this molecule an attractive therapeutic target for neurological disease. Thanks to the availability of sophisticated new genetic tools and selective pharmacological agents, we continue to learn that the function of TNF is complex, often dichotomous, with its soluble form (solTNF) acting primarily as a proinflammatory mediator detrimental to CNS integrity, and its membrane-bound form (tmTNF) sustaining beneficial reparative processes. Although much still needs to be learned, the emerging picture is that TNF’s function not only varies depending upon its cellular form, but also in relation to disease type and phase, and this must be taken into account to most effectively target TNF for therapeutic purposes.

The goal of this Special Issue is to provide a panorama of the ongoing efforts in elucidating the functions of TNF in neurological disease. We aim to cover a wide range of pathologies, both acute and chronic, and from traumatic to classically degenerative.

We look forward to your contributions.

Prof. Roberta Brambilla
Prof. Kate Lykke Lambertsen
Guest Editors

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Keywords

TNF
inflammation
neuroinflammation
CNS
cytokines
neurodegeneration
neuroprotection

Published Papers (9 papers)

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Research

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20 pages, 4117 KiB

Open AccessArticle

TNFR2 Signaling Regulates the Immunomodulatory Function of Oligodendrocyte Precursor Cells

by Haritha L. Desu, Placido Illiano, James S. Choi, Maureen C. Ascona, Han Gao, Jae K. Lee and Roberta Brambilla

Cells 2021, 10(7), 1785; https://doi.org/10.3390/cells10071785 - 15 Jul 2021

Cited by 18 | Viewed by 3235

Abstract

Multiple sclerosis (MS) is a neuroimmune disorder characterized by inflammation, CNS demyelination, and progressive neurodegeneration. Chronic MS patients exhibit impaired remyelination capacity, partly due to the changes that oligodendrocyte precursor cells (OPCs) undergo in response to the MS lesion environment. The cytokine tumor necrosis factor (TNF) is present in the MS-affected CNS and has been implicated in disease pathophysiology. Of the two active forms of TNF, transmembrane (tmTNF) and soluble (solTNF), tmTNF signals via TNFR2 mediating protective and reparative effects, including remyelination, whereas solTNF signals predominantly via TNFR1 promoting neurotoxicity. To better understand the mechanisms underlying repair failure in MS, we investigated the cellular responses of OPCs to inflammatory exposure and the specific role of TNFR2 signaling in their modulation. Following treatment of cultured OPCs with IFNγ, IL1β, and TNF, we observed, by RNA sequencing, marked inflammatory and immune activation of OPCs, accompanied by metabolic changes and dysregulation of their proliferation and differentiation programming. We also established the high likelihood of cell–cell interaction between OPCs and microglia in neuroinflammatory conditions, with OPCs able to produce chemokines that can recruit and activate microglia. Importantly, we showed that these functions are exacerbated when TNFR2 is ablated. Together, our data indicate that neuroinflammation leads OPCs to shift towards an immunomodulatory phenotype while diminishing their capacity to proliferate and differentiate, thus impairing their repair function. Furthermore, we demonstrated that TNFR2 plays a key role in this process, suggesting that boosting TNFR2 activation or its downstream signals could be an effective strategy to restore OPC reparative capacity in demyelinating disease. Full article

(This article belongs to the Special Issue Tumor Necrosis Factor (TNF) in Neurological Disorders)

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16 pages, 2629 KiB

Open AccessArticle

Changes in Cerebrospinal Fluid Balance of TNF and TNF Receptors in Naïve Multiple Sclerosis Patients: Early Involvement in Compartmentalised Intrathecal Inflammation

by Roberta Magliozzi, Francesco Pezzini, Mairi Pucci, Stefania Rossi, Francesco Facchiano, Damiano Marastoni, Martina Montagnana, Giuseppe Lippi, Richard Reynolds and Massimiliano Calabrese

Cells 2021, 10(7), 1712; https://doi.org/10.3390/cells10071712 - 06 Jul 2021

Cited by 12 | Viewed by 3129

Abstract

An imbalance of TNF signalling in the inflammatory milieu generated by meningeal immune cell infiltrates in the subarachnoid space in multiple sclerosis (MS), and its animal model may lead to increased cortical pathology. In order to explore whether this feature may be present from the early stages of MS and may be associated with the clinical outcome, the protein levels of TNF, sTNF-R1 and sTNF-R2 were assayed in CSF collected from 122 treatment-naïve MS patients and 36 subjects with other neurological conditions at diagnosis. Potential correlations with other CSF cytokines/chemokines and with clinical and imaging parameters at diagnosis (T0) and after 2 years of follow-up (T24) were evaluated. Significantly increased levels of TNF (fold change: 7.739; p < 0.001), sTNF-R1 (fold change: 1.693; p < 0.001) and sTNF-R2 (fold change: 2.189; p < 0.001) were detected in CSF of MS patients compared to the control group at T0. Increased TNF levels in CSF were significantly (p < 0.01) associated with increased EDSS change (r = 0.43), relapses (r = 0.48) and the appearance of white matter lesions (r = 0.49). CSF levels of TNFR1 were associated with cortical lesion volume (r = 0.41) at T0, as well as with new cortical lesions (r = 0.56), whilst no correlation could be found between TNFR2 levels in CSF and clinical or MRI features. Combined correlation and pathway analysis (ingenuity) of the CSF protein pattern associated with TNF expression (encompassing elevated levels of BAFF, IFN-γ, IL-1β, IL-10, IL-8, IL-16, CCL21, haptoglobin and fibrinogen) showed a particular relationship to the interaction between innate and adaptive immune response. The CSF sTNF-R1-associated pattern (encompassing high levels of CXCL13, TWEAK, LIGHT, IL-35, osteopontin, pentraxin-3, sCD163 and chitinase-3-L1) was mainly related to altered T cell and B cell signalling. Finally, the CSF TNFR2-associated pattern (encompassing high CSF levels of IFN-β, IFN-λ2, sIL-6Rα) was linked to Th cell differentiation and regulatory cytokine signalling. In conclusion, dysregulation of TNF and TNF-R1/2 pathways associates with specific clinical/MRI profiles and can be identified at a very early stage in MS patients, at the time of diagnosis, contributing to the prediction of the disease outcome. Full article

(This article belongs to the Special Issue Tumor Necrosis Factor (TNF) in Neurological Disorders)

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20 pages, 6287 KiB

Open AccessArticle

Bone Marrow-Derived IL-1Ra Increases TNF Levels Poststroke

by Christian Ulrich von Linstow, Sofie Mozart Hindkjær, Pernille Vinther Nielsen, Matilda Degn, Kate Lykke Lambertsen, Bente Finsen and Bettina Hjelm Clausen

Cells 2021, 10(4), 956; https://doi.org/10.3390/cells10040956 - 20 Apr 2021

Cited by 3 | Viewed by 3198

Abstract

Tumor necrosis factor (TNF) and interleukin-1 receptor antagonist (IL-1Ra) are key players in stroke, a disease in which cell-based therapies have shown great potential. Having shown an infarct-reducing effect of bone marrow (BM) cells, especially cells with high IL-1Ra expression, we here investigated the effect of BM cells on TNF and other stroke-related mediators in mice after transient middle cerebral artery occlusion (tMCAo) and in vitro using adult microglial cultures. We analyzed stroke-related genes and inflammatory mediators using qPCR stroke Tier panels, electrochemiluminescence, or enzyme-linked immunosorbent assays. We found a significant correlation and cellular colocalization between microglial-derived TNF and IL-1Ra, though IL-1Ra production was TNF independent. BM treatment significantly increased TNF, interleukin (IL)-10, and IL-4 levels, while C-X-C motif ligand 1 (CXCL1), IL-12p70, and Toll-like receptor 2 (TLR2) decreased, suggesting that BM treatment favors an anti-inflammatory environment. Hierarchical clustering identified Tnf and IL-1rn within the same gene cluster, and subsequent STRING analysis identified TLR2 as a shared receptor. Although IL-1Ra producing BM cells specifically modulated TNF levels, this was TLR2 independent. These results demonstrate BM cells as modulators of poststroke inflammation with beneficial effects on poststroke outcomes and place TNF and IL-1Ra as key players of the defense response after tMCAo. Full article

(This article belongs to the Special Issue Tumor Necrosis Factor (TNF) in Neurological Disorders)

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22 pages, 2481 KiB

Open AccessArticle

Leukocyte TNFR1 and TNFR2 Expression Contributes to the Peripheral Immune Response in Cases with Ischemic Stroke

by Rikke B. Hansen, Cathrine C. H. Laursen, Niala Nawaz, Jonna S. Madsen, Helle H. Nielsen, Christina Kruuse, Arne Møller, Matilda Degn and Kate L. Lambertsen

Cells 2021, 10(4), 861; https://doi.org/10.3390/cells10040861 - 09 Apr 2021

Cited by 9 | Viewed by 2751

Abstract

Tumor necrosis factor receptor 1 and 2 (TNFR1 and TNFR2) have been found in brain parenchyma of stroke patients, and plasma levels are increased in the acute phase of stroke. We evaluated associations between TNFR1 and TNFR2 plasma levels and stroke severity, infarct size, and functional outcome. Furthermore, we examined cellular expression of TNFR1 and TNFR2 on leukocyte subpopulations to explore the origin of the increased receptor levels. Blood samples were taken from 33 acute ischemic stroke patients and 10 healthy controls. TNFR1 and TNFR2 plasma concentrations were measured and correlated against the Scandinavian Stroke Scale at admission, infarct volume, and the modified Rankin Scale score three months after stroke onset. Classical, intermediate, and non-classical monocytes as well as neutrophils were purified, and cellular expression of TNFR1 and TNFR2 was examined using flow cytometry. TNFR1 and TNFR2 plasma levels were both increased after ischemic stroke, but we found no correlation with patient outcome measurements. Compared to healthy controls, ischemic stroke patients had decreased non-classical monocyte and neutrophil populations expressing TNFR1 and increased neutrophils expressing TNFR2, and decreased non-classical populations co-expressing both TNFR1 and TNFR2. This study supports the hypothesis of an acute immunological response orchestrated by the peripheral immune system following an ischemic stroke. However, the origin of the increased TNFR1 and TNFR2 plasma levels could not be clearly linked to peripheral monocytes or neutrophils. Future studies are needed and will help clarify the potential role as treatment target. Full article

(This article belongs to the Special Issue Tumor Necrosis Factor (TNF) in Neurological Disorders)

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18 pages, 2213 KiB

Open AccessArticle

Tumor Necrosis Factor (TNF) Is Required for Spatial Learning and Memory in Male Mice under Physiological, but Not Immune-Challenged Conditions

by Leda Mygind, Marianne Skov-Skov Bergh, Vivien Tejsi, Ramanan Vaitheeswaran, Kate L. Lambertsen, Bente Finsen and Athanasios Metaxas

Cells 2021, 10(3), 608; https://doi.org/10.3390/cells10030608 - 09 Mar 2021

Cited by 4 | Viewed by 2250

Abstract

Increasing evidence demonstrates that inflammatory cytokines—such as tumor necrosis factor (TNF)—are produced at low levels in the brain under physiological conditions and may be crucial for synaptic plasticity, neurogenesis, learning and memory. Here, we examined the effects of developmental TNF deletion on spatial learning and memory using 11–13-month-old TNF knockout (KO) and C57BL6/J wild-type (WT) mice. The animals were tested in the Barnes maze (BM) arena under baseline conditions and 48 h following an injection of the endotoxin lipopolysaccharide (LPS), which was administered at a dose of 0.5 mg/kg. Vehicle-treated KO mice were impaired compared to WT mice during the acquisition and memory-probing phases of the BM test. No behavioral differences were observed between WT and TNF-KO mice after LPS treatment. Moreover, there were no differences in the hippocampal content of glutamate and noradrenaline between groups. The effects of TNF deletion on spatial learning and memory were observed in male, but not female mice, which were not different compared to WT mice under baseline conditions. These results indicate that TNF is required for spatial learning and memory in male mice under physiological, non-inflammatory conditions, however not following the administration of LPS. Inflammatory signalling can thereby modulate spatial cognition in male subjects, highlighting the importance of sex- and probably age-stratified analysis when examining the role of TNF in the brain. Full article

(This article belongs to the Special Issue Tumor Necrosis Factor (TNF) in Neurological Disorders)

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23 pages, 3350 KiB

Open AccessArticle

Conditional Ablation of Myeloid TNF Improves Functional Outcome and Decreases Lesion Size after Spinal Cord Injury in Mice

by Ditte Gry Ellman, Minna Christiansen Lund, Maiken Nissen, Pernille Sveistrup Nielsen, Charlotte Sørensen, Emilie Boye Lester, Estrid Thougaard, Louise Helskov Jørgensen, Sergei A. Nedospasov, Ditte Caroline Andersen, Jane Stubbe, Roberta Brambilla, Matilda Degn and Kate Lykke Lambertsen

Cells 2020, 9(11), 2407; https://doi.org/10.3390/cells9112407 - 03 Nov 2020

Cited by 13 | Viewed by 2442

Abstract

Spinal cord injury (SCI) is a devastating condition consisting of an instant primary mechanical injury followed by a secondary injury that progresses for weeks to months. The cytokine tumor necrosis factor (TNF) plays an important role in the pathophysiology of SCI. We investigated the effect of myeloid TNF ablation (peripheral myeloid cells (macrophages and neutrophils) and microglia) versus central myeloid TNF ablation (microglia) in a SCI contusion model. We show that TNF ablation in macrophages and neutrophils leads to reduced lesion volume and improved functional outcome after SCI. In contrast, TNF ablation in microglia only or TNF deficiency in all cells had no effect. TNF levels tended to be decreased 3 h post-SCI in mice with peripheral myeloid TNF ablation and was significantly decreased 3 days after SCI. Leukocyte and microglia populations and all other cytokines (IL-1β, IL-2, IL-4, IL-5, IL-6, IL-10, IL-12, and IFNγ) and chemokines (CCL2, CCL5, and CXCL1) investigated, in addition to TNFR1 and TNFR2, were comparable between genotypes. Analysis of post-SCI signaling cascades demonstrated that the MAPK kinase SAPK/JNK decreased and neuronal Bcl-XL levels increased post-SCI in mice with ablation of TNF in peripheral myeloid cells. These findings demonstrate that peripheral myeloid cell-derived TNF is pathogenic in SCI. Full article

(This article belongs to the Special Issue Tumor Necrosis Factor (TNF) in Neurological Disorders)

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Review

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19 pages, 1548 KiB

Open AccessReview

Tumor Necrosis Factor Alpha in Amyotrophic Lateral Sclerosis: Friend or Foe?

by Giulia Guidotti, Chiara Scarlata, Liliana Brambilla and Daniela Rossi

Cells 2021, 10(3), 518; https://doi.org/10.3390/cells10030518 - 01 Mar 2021

Cited by 20 | Viewed by 4858

Abstract

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by a massive neuroinflammatory reaction, which plays a key role in the progression of the disease. One of the major mediators of the inflammatory response is the pleiotropic cytokine tumor necrosis factor α (TNFα), mainly released within the central nervous system (CNS) by reactive astrocytes and microglia. Increased levels of TNFα and its receptors (TNFR1 and TNFR2) have been described in plasma, serum, cerebrospinal fluid and CNS tissue from both ALS patients and transgenic animal models of disease. However, the precise role exerted by TNFα in the context of ALS is still highly controversial, since both protective and detrimental functions have been reported. These opposing actions depend on multiple factors, among which includes the type of TNFα receptor activated. In fact, TNFR2 seems to mediate a harmful role being involved in motor neuron cell death, whereas TNFR1 signaling mediates neuroprotective effects, promoting the expression and secretion of trophic factors. This suggests that a better understanding of the cytokine impact on ALS progression may enable the development of effective therapies aimed at strengthening the protective roles of TNFα and at suppressing the detrimental ones. Full article

(This article belongs to the Special Issue Tumor Necrosis Factor (TNF) in Neurological Disorders)

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26 pages, 944 KiB

Open AccessReview

Re-Examining the Role of TNF in MS Pathogenesis and Therapy

by Diego Fresegna, Silvia Bullitta, Alessandra Musella, Francesca Romana Rizzo, Francesca De Vito, Livia Guadalupi, Silvia Caioli, Sara Balletta, Krizia Sanna, Ettore Dolcetti, Valentina Vanni, Antonio Bruno, Fabio Buttari, Mario Stampanoni Bassi, Georgia Mandolesi, Diego Centonze and Antonietta Gentile

Cells 2020, 9(10), 2290; https://doi.org/10.3390/cells9102290 - 14 Oct 2020

Cited by 51 | Viewed by 4794

Abstract

Multiple sclerosis (MS) is a common neurological disorder of putative autoimmune origin. Clinical and experimental studies delineate abnormal expression of specific cytokines over the course of the disease. One major cytokine that has been shown to play a pivotal role in MS is tumor necrosis factor (TNF). TNF is a pleiotropic cytokine regulating many physiological and pathological functions of both the immune system and the central nervous system (CNS). Convincing evidence from studies in human and experimental MS have demonstrated the involvement of TNF in various pathological hallmarks of MS, including immune dysregulation, demyelination, synaptopathy and neuroinflammation. However, due to the complexity of TNF signaling, which includes two-ligands (soluble and transmembrane TNF) and two receptors, namely TNF receptor type-1 (TNFR1) and type-2 (TNFR2), and due to its cell- and context-differential expression, targeting the TNF system in MS is an ongoing challenge. This review summarizes the evidence on the pathophysiological role of TNF in MS and in different MS animal models, with a special focus on pharmacological treatment aimed at controlling the dysregulated TNF signaling in this neurological disorder. Full article

(This article belongs to the Special Issue Tumor Necrosis Factor (TNF) in Neurological Disorders)

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22 pages, 2589 KiB

Open AccessReview

TNF Production and Release from Microglia via Extracellular Vesicles: Impact on Brain Functions

by Stefano Raffaele, Marta Lombardi, Claudia Verderio and Marta Fumagalli

Cells 2020, 9(10), 2145; https://doi.org/10.3390/cells9102145 - 23 Sep 2020

Cited by 56 | Viewed by 8340

Abstract

Tumor necrosis factor (TNF) is a pleiotropic cytokine powerfully influencing diverse processes of the central nervous system (CNS) under both physiological and pathological conditions. Here, we analyze current literature describing the molecular processes involved in TNF synthesis and release from microglia, the resident immune cells of the CNS and the main source of this cytokine both in brain development and neurodegenerative diseases. A special attention has been given to the unconventional vesicular pathway of TNF, based on the emerging role of microglia-derived extracellular vesicles (EVs) in the propagation of inflammatory signals and in mediating cell-to-cell communication. Moreover, we describe the contribution of microglial TNF in regulating important CNS functions, including the neuroinflammatory response following brain injury, the neuronal circuit formation and synaptic plasticity, and the processes of myelin damage and repair. Specifically, the available data on the functions mediated by microglial EVs carrying TNF have been scrutinized to gain insights on possible novel therapeutic strategies targeting TNF to foster CNS repair. Full article

(This article belongs to the Special Issue Tumor Necrosis Factor (TNF) in Neurological Disorders)

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