Conditional Ablation of Myeloid TNF Improves Functional Outcome and Decreases Lesion Size after Spinal Cord Injury in Mice.
Ditte Gry EllmanMinna Christiansen LundMaiken NissenPernille Sveistrup NielsenCharlotte SørensenEmilie Boye LesterEstrid ThougaardLouise Helskov JørgensenSergei A NedospasovDitte Caroline AndersenJane StubbeRoberta BrambillaMatilda DegnKate Lykke LambertsenPublished in: Cells (2020)
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.
Keyphrases
- spinal cord injury
- rheumatoid arthritis
- neuropathic pain
- dendritic cells
- bone marrow
- induced apoptosis
- acute myeloid leukemia
- spinal cord
- cell cycle arrest
- signaling pathway
- metabolic syndrome
- magnetic resonance
- oxidative stress
- skeletal muscle
- computed tomography
- type diabetes
- cell death
- adipose tissue
- atrial fibrillation
- high fat diet induced
- catheter ablation
- tyrosine kinase
- peripheral blood
- drug induced