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

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

*Corresponding author for this work

Research output: Contribution to journalJournal articleResearchpeer-review

16 Downloads (Pure)

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.

Original languageEnglish
Article number2407
JournalCells
Volume9
Issue number11
Number of pages23
ISSN2073-4409
DOIs
Publication statusPublished - 3. Nov 2020

Keywords

  • functional outcome
  • myeloid cells
  • spinal cord injury
  • tumor necrosis factor

Fingerprint Dive into the research topics of 'Conditional Ablation of Myeloid TNF Improves Functional Outcome and Decreases Lesion Size after Spinal Cord Injury in Mice'. Together they form a unique fingerprint.

Cite this