Tumor Necrosis Factor-alpha and the Roles it Plays in Homeostatic and Degenerative Processes Within the Central Nervous System

Tumor Necrosis Factor-alpha (TNF-alpha) is a prototypic pro-inflammatory cytokine involved in the innate immune response. TNF-alpha ligation and downstream signaling with one of its cognate receptors, TNF-RI or TNF-RII, modulates fundamental processes in the brain including synapse formation and regulation, neurogenesis, regeneration, and general maintenance of the central nervous system (CNS). During states of chronic neuroinflammation, extensive experimental evidence implicates TNF-alpha as a key mediator in disease progression, gliosis, demyelination, inflammation, blood-brain-barrier deterioration, and cell death. This review explores the complex roles of TNF-alpha in the CNS under normal physiologic conditions and during neurodegeneration. We focus our discussion on Multiple Sclerosis, Parkinson's disease, and Alzheimer's disease, relaying the outcomes of preclinical and clinical testing of TNF-alpha directed therapeutic strategies, and arguing that despite the wealth of functions attributed to this central cytokine, surprisingly little is known about the cell type- and stage-specific roles of TNF-alpha in these debilitating disorders.