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The Role of Tumor Necrosis Factor Following Spinal Cord Injury: A Systematic Review

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Abstract

Pre-clinical studies place tumor necrosis factor (TNF) as a central player in the inflammatory response after spinal cord injury (SCI), and blocking its production and/or activity has been proposed as a possible treatment option after SCI. This systematic review provides an overview of the literature on the temporal and cellular expression of TNF after SCI and clarifies the potential for its therapeutic manipulation in SCI. A systematic search was performed in EMBASE (Ovid), MEDLINE (Ovid), and Web of Science (Core Collection). The search terms were the MeSH forms of tumor necrosis factor and spinal cord injury in the different databases, and the last search was performed on February 3, 2021. We found twenty-four articles examining the expression of TNF, with most using a thoracic contusive SCI model in rodents. Two articles described the expression of TNF receptors in the acute phase after SCI. Twenty-one articles described the manipulation of TNF signaling using genetic knock-out, pharmaceutical inhibition, or gain-of-function approaches. Overall, TNF expression increased rapidly after SCI, within the first hours, in resident cells (neurons, astrocytes, oligodendrocytes, and microglia) and again in macrophages in the chronic phase after injury. The review underscores the complexity of TNF’s role after SCI and indicates that TNF inhibition is a promising therapeutic option. This review concludes that TNF plays a significant role in the inflammatory response after SCI and suggests that targeting TNF signaling is a feasible therapeutic approach.

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Abbreviations

AIS:

American spinal injury association (ASIA) impairment scale

Arg 1:

Arginase-1

CD:

Cluster of differentiation

CNS:

Central nervous system

CSF:

Cerebrospinal fluid

CXCL1:

C-X-C motif chemokine ligand 1

GFAP:

Glial fibrillary acidic protein

i.m.:

Intramuscular

i.p.:

Intraperitoneal

Iba1:

Ionized calcium-binding adaptor molecule 1

IL:

Interleukin

KO:

Knock-out

MAP2:

Microtubule-associated protein 2

MDA:

Malondialdehyde

PRISMA:

Preferred reporting items for systematic reviews and meta-analysis

qPCR:

Quantitative polymerase chain reaction

ROS:

Reactive oxygen species

RT-PCR:

Reverse transcriptase-polymerase chain reaction

s.c.:

Subcutaneous

SCI:

Spinal cord injury

solTNF:

Soluble tumor necrosis factor

TACE:

Tumor necrosis factor-alpha converting enzyme

tmTNF:

Transmembrane tumor necrosis factor

TNF:

Tumor necrosis factor

TNFR:

Tumor necrosis factor receptor

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Acknowledgements

Silas Arlt Tvingsholm is acknowledged for help with graphical designs and Ulla Damgaard Munk is acknowledged for the technical assistance. Claire Gudex is acknowledged for proofreading.

Funding

The funding source for this work was from the Lundbeck Foundation (Grant No. R230-2016-3019); Faculty of Health Science, SDU, Denmark; Desirée and Niels Yde’s Foundation, Denmark; Fonden for Lægevidenskabens Fremme; Overlægerådets legatudvalg, Odense University Hospital, Denmark; Auguststinus Fonden, Denmark; Kong Christian den Tiendes Fond, Denmark.

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Authors and Affiliations

  1. Neurobiology Research, Institute of Molecular Medicine, University of Southern Denmark, Odense, Denmark

    Minna Christiansen Lund, Bettina Hjelm Clausen, Roberta Brambilla & Kate Lykke Lambertsen

  2. BRIGDE—Brain Research—Inter-Disciplinary Guided Excellence, Department of Clinical Research, University of Southern Denmark, Odense, Denmark

    Bettina Hjelm Clausen, Roberta Brambilla & Kate Lykke Lambertsen

  3. The Miami Project to Cure Paralysis, Department of Neurological Surgery, University of Miami Miller School of Medicine, Miami, FL, 33136, USA

    Roberta Brambilla

  4. Neuroscience Program, University of Miami Miller School of Medicine, Miami, FL, 33136, USA

    Roberta Brambilla

  5. Department of Neurology, Odense University Hospital, J.B. Winsløwsvej 21 st., 5000, Odense, Denmark

    Kate Lykke Lambertsen

Authors
  1. Minna Christiansen Lund
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  2. Bettina Hjelm Clausen
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  3. Roberta Brambilla
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  4. Kate Lykke Lambertsen
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Contributions

MCL and KLL performed the search and analyzed and interpreted the data. RB contributed with human postmortem spinal cord tissue sections. MCL, KLL, and BHC wrote the manuscript and all authors reviewed and edited the manuscript.

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Correspondence to Kate Lykke Lambertsen.

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The authors declare no competing interests.

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The authors declare that they have no competing interests.

Ethical Approval

Paraffin-embedded postmortem human spinal cord samples are obtained from The Miami Project Human Core Bank at the University of Miami Miller School of Medicine managed by Alexander Marcillo, MD, and Yan Shi, MSc.

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Lund, M.C., Clausen, B.H., Brambilla, R. et al. The Role of Tumor Necrosis Factor Following Spinal Cord Injury: A Systematic Review. Cell Mol Neurobiol 43, 925–950 (2023). https://doi.org/10.1007/s10571-022-01229-0

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  • DOI: https://doi.org/10.1007/s10571-022-01229-0

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