TNF promotes M1 polarization through mitochondrial metabolism in injured spinal cord

Macrophages and microglia (M/Ms) in the injured spinal cord maintain a predominantly neurotoxic M1 phenotype that is disadvantageous to repair in the development of spinal cord injury (SCI). It has been reported that tumor necrosis factor (TNF) that polarize M/Ms toward M1 state in various disorders. In this study, we found that ablation of TNF endorsed the beneficial conversion from M1 to M2 phenotype and improved the mitochondrial metabolism in vivo and in vitro. In addition, PGC-1α that accumulates in TNF null mice, a major participant of mitochondrial metabolism, downregulated ROS activity and the expressions of M1-specific mRNA. Moreover, the absence of TNF upgraded the morphology and quantity of damaged mitochondria and rapidly switched to M2 phenotype as compare to administration of N-Acetyl-l-cysteine (NAC). Furthermore, systemic application of TPEN showed that increased ratio of M1 M/Ms. These combined results supporting predominant and prolonged TNF expression that is destructive to recovery after SCI. These results indicated that TNF would have great potential immunomodulatory for the treatment of SCI.