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

Cells. 2020 Nov 3;9(11):2407. doi: 10.3390/cells9112407.


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.

Keywords: functional outcome; myeloid cells; spinal cord injury; tumor necrosis factor.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CX3C Chemokine Receptor 1 / metabolism
  • Gene Deletion*
  • Inflammation / pathology
  • MAP Kinase Signaling System
  • Macrophages / metabolism
  • Mice
  • Microglia / metabolism
  • Microglia / pathology
  • Motor Activity
  • Myeloid Cells / metabolism*
  • Neutrophils / metabolism
  • Proto-Oncogene Proteins c-akt / metabolism
  • Recovery of Function
  • STAT Transcription Factors / metabolism
  • Spinal Cord / pathology
  • Spinal Cord Injuries / pathology*
  • Spinal Cord Injuries / physiopathology*
  • Tumor Necrosis Factor-alpha / metabolism*
  • bcl-X Protein / metabolism


  • CX3C Chemokine Receptor 1
  • Cx3cr1 protein, mouse
  • STAT Transcription Factors
  • Tumor Necrosis Factor-alpha
  • bcl-X Protein
  • Proto-Oncogene Proteins c-akt